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Immunogen Antibody Conjugate Patent Survives IPR

11.02.15 Posted in PTAB by

Phigenix, Inc. v. Immugen, Inc., IPR2014-00676 (PTAB 10/27/2015)

This IPR involved US Patent 8,337,856, which claims antibody-toxin immunogates for the treatment of cancer. In a final written decision by the PTAB, the patent survives an IPR challenge from Phigenix. The Board finds that “general statements” in an older reference did not offer a reasonable expectation of success. This holding suggests that the PTAB may be pro-patentee in the “unpredictable” chemical and biological arts.

The ‘856 patent (apparently filed in March, 2000) covers immunoconjugates comprising an anti-ErbB antibody, such as the humanized anti-ErbB2 antibody known as HERCEPTIN® (huMAb4D5-8, also called “trastuzumab”), linked to a maytansinoid toxin.  The ErbB family of receptor tyrosine kinases mediate cell growth, differentiation, and survival. Overexpression of ErbB2 on cell surfaces can lead to cancer in humans, such as certain breast and ovarian cancers. The maytansinoid toxin is highly cytotoxic, and not useful as a drug administered alone because of poor selectivity for tumors, which causes systematic side effects.

The IPR was instituted after the Board concluded there was a reasonable likelihood of success that the challenged claims would have been obvious under 35 U.S.C. § 103 over “Chari 1992” in view of the HERCEPTIN® label and other references. Chari 1992 is a journal article.

Chari 1992 described immunoconjugates of an anti-ErbB2 mouse monoclonal antibody conjugated to DM1, a maytansinoid toxin. Chari 1992 also stated that the development of humanized antibodies could produce more desirable therapeutic conjugates.

The HERCEPTIN® label describes trastuzumab as a humanized mouse antibody indicated for the treatment of patients with metastatic breast cancer that overexpress the HER2 protein and have been treated with other chemotherapy.

Obviousness Analysis

Phigenix contended that Chari 1992 taught all limitations of the ‘856 patent except the specific antibody huMAb4D5-8 and a pharmaceutical carrier. Relying an on expert declaration, Phigenix contended that it would have been obvious at the time the ‘856 patent was filed to substitute a humanized antibody to produce the claim-recited huMAb4D5-8. Specifically, Phigenix contended that (1) it was known (from Chari 1992) that humanized monoclonal antibodies had advantages over murine antibodies; (2) huMAb4D5-8 selectively bound to HER2 (an alternative terminology for erbB2); and (3) clinical studies have shown that huMAb4D5-8 worked well in combination with microtubule-directed chemotherapy agents. Phigenix further argued that there was a reasonable expectation of success.

Immunogen responded that Phigenix failed to make a prima facie case of obviousness, primarily because a POSA would not have had a reason to substitute the mouse antibody in Chari 1992 with huMAb4D5-8.

The Board found Immunogen’s argument persuasive, because of “Pai-Scherf 1999” (a journal article) which taught that HERCEPTIN®-maytansinoid immunoconjugates would have been expected to exhibit unacceptable levels of antigen-dependent toxicity in normal human liver tissue (hepatoxicity), presumably due to the presence of erbB2 on hepatocytes.

Phigenix responded that Pai-Scherf 1999 taught a fusion-protein, not an antibody-drug conjugate, but the Board was not persuaded by this argument because of the general teaching of targeting of tumors that express erbB2 with antibodies armed with cytoxic agents.

What is interesting here is that the Board rejects Phigenix’ main argument that the general statements (not “teachings”; emphasis added) of Chari 1992 in view of teachings years later in the HERCEPTIN® Label, Pai-Scherf 1999, and other references regarding liver toxicities, would have motivated an ordinary artisan to substitute the mouse TA.1 antibody in the immunoconjugate of Chari 1992 with HERCEPTIN® on the basis that one would have expected that modified immunoconjugate to work to treat human tumors.  The Board also was not persuaded by the other references cited by Phigenix, because such studies would not have provided an ordinary artisan with adequate (emphasis added) information regarding human toxicity in vivo. Immunogen also pointed to evidence that researchers had targeted tumors with immunoconjugates for about 40 years before the ’856 patent without success.  Immunogen also provided evidence showing that preparing any antibody-toxin immunoconjugate for use in the treatment of human tumors was difficult and unpredictable.


The Board comes down on the side of the unpredictability of the chemical and biological arts, holding that “general statements” (emphasis added), not “teachings,” of an older reference did not offer a reasonable expectation of success in an area, antibody-drug conjugates, where many years of research were unsuccessful. Thus, despite hints in the prior art of a direction of research, those hints were insufficient to overcome the reasonable expectation prong of the KSR analysis.  The general statements and hints were not a finite number of identified, predictable solutions that would have to be satisfied to meet the reasonable expectation of success that render the claims obvious under KSR.

This holding suggests that the PTAB may be pro-patentee in the chemical and biological arts.

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Crowd Funding Boost? Crowd Funding Patent Invalidated by Kickstarter

07.01.15 Posted in District Court Opinions, News by

Crowd Funding Patent Claims Abstract Ideas

Judge Failla at the Southern District of New York agreed with Kickstarter that US Patent  7,885,887, claiming crowd funding, is invalid under §101. “The ‘887 Patent claims only the abstract and time-honored concept of patronage, and even the addition of an element of computer use is insufficient to render it valid under Section 101 of the Patent Act, 35 U.S.C. § 101.” Kickstarter’s motion for summary judgment is granted.

Kickstarter, Inc. v. Fan Funded, LLC, et. al., No. 1:11-cv-06909, SDNY, Judge Failla, 6/29/2015

The original opinion is here: nysd-1-11-cv-06909-111

Cittone & Chinta LLP

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Apotex loses IPR on Prodrug Obviousness (Institution Denied)

06.29.15 Posted in PTAB by

Apotex Inc. v. Merck Sharpe & Dohme Corp., IPR2015-00419, Patent 5,691,336, Institution of IPR denied, 6/25/2015

Merck owns US patent 5691336, directed to tachykinin receptor antagonists. This patent is listed in the Orange Book as claiming the drug substance and drug product of fosaprepitant dimeglumine, sold under the brand name “Emend.” Fosaprepitant is a phosphoramidate prodrug of aprepitant, an antiemetic drug. The ‘336 patent received a patent term extension on under 35 USC § 156 for five years, so it expires on March 4, 2019. Merck has asserted this patent against several other generic copyists, but not against Apotex. It’s not stated if Apotex has already filed a PIV certification against this product.

Petitioner Apotex asserted that claims directed to the marketed product were obvious. The primary argument was that the Dorn ‘699 patent disclosed the structure of aprepitant, and that the Murdock ‘082 patent disclosed phosphoramidate prodrugs to improve the aqueous solubility of a parent nitrogenous compound. Apotex argued that it was obvious modify the parent compound aprepitant with the Murdock ‘082 prodrugs to arrive at the claimed invention (fosaprepitant).

The opinion cited the two-part analysis elucidated in Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291–93 (Fed. Cir. 2012) for this kind of analysis. The Otsuka test asks of a person of ordinary skill would (1) select an appropriate lead compound, and (2) if there is a reason to modify the lead compound to arrive at the claimed compound.

The PTAB finds that the lead compound selection prong fails in this case. Dorn ‘699 disclosed a broad genus of compounds. Aprepitant was compound 96 in Dorn ‘699. Apotex argued that there was a narrowed range of preferred substituents that encompassed compound 96, but the PTAB agreed with Merck that a “skilled artisan would not have picked compound 96 from the hundreds of compounds listed in [Dorn ‘699].” Slip op. at 8–9. Dorn ‘699 disclosed 600 specific compounds. There was no biological data pointing to compound 96, and other leads at the time of the ‘336 patent invention pointed to other likely compounds. So “compound 96 could not have served as ‘a natural choice for further development efforts.’” Slip op. at 9. An additional factor is that aprepitant was not a known active drug until well after the ‘336 patent issued (see fn 9).

Other obviousness arguments all relied on Dorn ‘699 for selecting compound 96 as the lead compound, and therefore all fail also.

The Board concludes that Petitioner (Apotex) did not establish a reasonable likelihood that it would prevail in showing the unpatentability of the claims in dispute, so the IPR is dismissed. The ‘336 patent is not obvious.


This decision is in contrast to Bristol Myers Squibb v Teva, 752 F.3d 967 (Fed. Cir. 2014), where the Federal Circuit held the structure of entecavir to be obvious. The court in BMS determined that there was a valid lead compound, and valid reasons to modify that compound. Apotex made similar arguments in this fosaprepitant case.

So why did the court in BMS find a lead compound where none was found by the PTAB in this fosaprepitant case? There is no clear conclusion here. On one hand, the references providing potential lead compounds for entecavir were not the kind expansive disclosure that the Dorn ‘699 patent appears to be. So the court was able to focus on a much narrower set of structures. But on the other hand, entecavir was not a prodrug. An argument could be made that there are a limited set of moieties useful to impart useful features on a parent structure, for example increasing solubility, increasing bioavailability, and preventing metabolism in the gut. So modifying a parent to form a pro-drug is more likely to be obvious, assuming the parent is an identified lead compound. Of course, in this fosaprepitant case, the Board held that there was no valid lead compound.

This case suggests that patent challengers seeking to invalidate a novel chemical structure patent will have a tough time at the PTAB.

Citation: Apotex Inc. v. Merck Sharpe & Dohme Corp., IPR2015-00419, Patent 5,691,336, Institution of IPR denied, 6/25/2015

Download the decision here: Apotex v Merck IPR2015-00419 -14

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You think your competitor’s patent is junk? Don’t tell it to the judge

06.08.15 Posted in Supreme Court Opinions by

Commentary by James P. Demers

On May 26, 2015, the U.S. Supreme Court issued a decision in a patent case, Commil USA, LLC v. Cisco Systems, Inc., in which the Court held that a good faith belief that a patent is invalid is not a defense against a charge of patent infringement.

The history of the dispute is long and torturous, involving two trials and a series of appeals dating back to 2007, but the facts of the case are simple enough:  Commil owns a patent on a method of operating a network of wireless routers, and Cisco sold equipment to its customers that used the method and therefore infringed the patent.  Commil duly brought suit, in the Eastern District of Texas, accusing Cisco of directly infringing the patent and also of inducing their customers to infringe.  It was the latter charge that led to the case at hand.

Cisco made the usual attempts, in the Patent Office and in the courts, to have Commil’s patent declared invalid, but did not succeed.  At trial on the induced infringement charge, Cisco attempted to present evidence that they had held a “good faith belief” that Commil’s patent was not valid, intending to argue that this was a valid defense.  The court refused to enter the evidence, and instructed the jury that they could find inducement if “Cisco actually intended to cause . . . direct infringement [by its customers],” and if “Cisco knew or should have known that its actions would induce actual infringement.”  The jury returned a verdict for Commil on induced infringement and awarded $63.7 million in damages.

On appeal, a 3-judge panel of the U.S. Court of Appeals for the Federal Circuit (“CAFC”) concluded it was error for the District Court to have instructed the jury that Cisco could be liable for induced infringement if it “knew or should have known” that its customers would infringe the patent.  The panel held that induced infringement requires “knowledge that the induced acts constitute patent infringement,” a standard established by the Supreme Court in a 2011 decision, Global-Tech Appliances, Inc. v. SEB S.A.  But how is “knowing that your customers will infringe” different from “knowing that the induced acts constitute infringement”?

What the CAFC judges were getting at was the legal concept of scienter – the state of mind of the accused party (in this case, Cisco).  According to the CAFC panel, in order to actually know that the acts of their customers will constitute infringement, Cisco would first have had to know that Commil’s patent was, in actual fact, valid.  The panel reasoned that Cisco, having a good-faith belief that the patent was not valid, could not have truly “known” that its customers were infringing, because an invalid patent cannot be infringed – indeed, there is no patent to infringe.  Commil appealed this decision.

The Supreme Court, in no uncertain terms, disagreed with the CAFC panel, and vacated their decision, handing the victory, finally, to Commil.  “The question the Court confronts today concerns whether a defendant’s belief regarding patent validity is a defense to a claim of induced infringement.  It is not.  The scienter element for induced infringement concerns infringement; that is a different issue than validity.”

What it means to you

At this point, you might be thinking, “OK, this might be fascinating material for patent attorneys to ponder, but what’s the message for me and my business?”  The lesson is that when you’re accused of infringing a patent, or of inducing your customers to infringe a patent, it doesn’t matter what you think about the quality of the patent.  You can be charged with “knowing” that you or your customers are infringing it, even if you’re convinced that the patent is junk.  And it will not matter a bit if you have a written opinion from the best (or most expensive) patent attorneys in the country, assuring you that it is junk.

To be sure, you may prevail if the patent is, in fact, declared invalid – but that’s an entirely separate question, decided by different rules applied to different facts.  And a competent opinion of counsel on validity, while it can’t obviate infringement, can significantly reduce the damages you might have to pay.  Patent law is full of such critical subtleties, which is why it is essential that you promptly consult with an experienced patent attorney any time you’re accused of patent infringement (or if you think you may be infringing someone else’s patent).

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Means-Plus-Function Software Claims Must Have an Underlying Algorithm

05.08.15 Posted in Federal Circuit Opinions by

All claims in EON’s patent were found to be invalid because means-plus-function claims describing complex computer functionality are indefinite without algorithms to provide structure to the claims. Eon Corp. IP Holding LLC v. AT&T Mobility LLC, No. 2014-1392 (Fed. Cir. 5/6/2015).

EON owns US patent 5663757, issued 9/2/1997, directed to software in a “local subscriber data processing station,” that pertains to interactive TV features, like audience participation, voting, and purchasing of goods. In 2010, EON asserted this patent against smartphone manufacturers and cellular telephone providers, alleging they were infringing.

At the Delaware District Court, following the claim construction hearing, the court granted summary judgment that all the claims were invalid as indefinite. Eight terms were held to be indefinite. For example, the first one listed is: “means under control of said replaceable software means for indicating acknowledging shipment of an order from a remote station.”

On appeal, the Federal Circuit panel (Prost, Newman, and Bryson, opinion by Prost) upheld the District Court, relying largely on WMS Gaming Inc. v. Int’l Game Tech., 184 F.3d 1339-1348-49 (Fed. Cir. 1999) which set out a rule that the corresponding structure for a function performed by a software algorithm is the algorithm itself. EON’s problem is that there were no algorithms in the specification or claims.

EON argued that the “Katz Exception” applied (In re Katz, 639 F.3d 1303 (Fed. Cir. 2011)), which held that a standard microprocessor can serve as sufficient structure for “functions [that] can be achieved by any general purpose computer without special programming,” like “processing,” “receiving,” etc. But this panel describes Katz as a narrow exception to the WMS Gaming rule. The opinion cites several cases held indefinite under the WMS Gaming rule for failure to disclose a sufficient algorithm. Under Katz, a microprocessor or general purpose computer lends sufficient structure only to basic functions of a microprocessor. All other computer-implemented functions require disclosure of an algorithm.

The panel concludes that the disclosure of a general purpose computer or a microprocessor as corresponding structure for a software function does nothing to limit the scope of the claim and “avoid pure functional claiming.” So, “when a patentee invokes means-plus-function claiming to recite a software function, it accedes to the reciprocal obligation of disclosing a sufficient algorithm as corresponding structure.”

The panel affirms the district court finding that each of the eight claim terms at issue recited complicated, customized computer software. So there is no clear error in the district court’s factual findings, or ultimate conclusion of indefiniteness. All claims of the ‘757 patent are invalid.


The takeaway here for patent drafters is to be careful with means-plus-function claiming, and with software patents generally, to ensure that sufficient structure is provided in the specification to enable a person skilled in the art to practice the invention. The court finds that the patentee did not do that here, resulting in “pure functional claiming,” i.e., impermissibly attempting to claim mere ideas. So with patents that recite computer controlled functions, some minimal discussion of how the result will be obtained should be provided. Although this case uses the term algorithm, other representations of computer programming, like a flow chart, a set of if-then statements, or computer code (even if just snippets), would probably suffice.

While this case is limited to means-plus-function claiming, the same principle probably applies to any software claiming. Good drafters will use an algorithm or other representation of computer instructions in the claims or disclosure to provide sufficient structure and support to the claims.

For challengers of software patents, with or without means-plus-function claiming, look for some type of algorithm or computer instructions that support and give structure to a claimed function. The absence of sufficient disclosure can be an opening for a challenge based on written description or indefiniteness.

With patents (like the patent in this case) filed before the development of modern technologies, for example high speed wireless networking or smartphones, visionaries may have conceived of good ideas, but had no idea how such ideas would be implemented. For such inventors, means-plus-function claiming was an attractive tool to describe the concepts in the belief that the details would be worked out in the future by a hypothetical person of ordinary skill. These patents may be vulnerable to the kind of challenge raised in this case.

Case citation:

Eon Corp. IP Holding LLC v. AT&T Mobility LLC, No. 2014-1392 (Fed. Cir. 5/6/2015)

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Comments Off on Apotex Bid to Steal Mylan Exclusivity on Benicar

Apotex Bid to Steal Mylan Exclusivity on Benicar

04.23.15 Posted in Federal Circuit Opinions by

In this matter, Mylan is sitting on a likely 180-day exclusivity for being the first-to-file generic for Benicar®, olmesartan medoximil. Apotex has now initiated a declaratory judgment action attempting to trigger a forfeiture event for this product. If Apotex is successful, Mylan could lose its exclusivity.

The Orange Book patents for this product are straightforward. US5616599 expires covers the compound and expires 10/25/2016 with pediatric exclusivity, and US6878703 expires 11/19/2021 and covers methods of use. The patents are owned by Daiichi.

Mylan was the first-to-file, in April 2006. Mylan sent Daiichi the required PIV notice. Daiichi responded by suing Mylan for patent infringement on the ‘599 patent. But Daiichi filed a statutory disclaimer to the ‘703 patent, so the ‘703 patent was not litigated. Daiichi prevailed in that litigation, so Mylan’s earliest entry date is on the expiry of the ‘599 patent. Mylan’s PIV certification remains intact with respect to the ‘703 patent, so Mylan is eligible for the 180-day exclusivity. No forfeiture event applied to Mylan because the ‘703 patent was not litigated (until now).

Apotex was a subsequent ANDA filer, and filed a PIII to the ‘599 and a PIV to the ‘703 patent. Daiichi did not sue Apotex – the ‘703 patent was disclaimed.

So Apotex, seeking to trigger a forfeiture event that would not otherwise occur, filed a declaratory judgment action seeking a declaration that its ANDA did not infringe the ‘703 patent. If successful, this could trigger the forfeiture under 21 USC §355(j)(5)(D)(i)(bb)(AA), of failure to market the product within 75 days of a decision from which no appeal (except certiorari) can be taken that the patent is invalid or not infringed. If the forfeiture is triggered, Mylan loses its exclusivity and Apotex can enter the market earlier than it would if it had to wait for Mylan’s exclusivity to run.

At the district court, Mylan won a dismissal on the ground that Apotex could not infringe a disclaimed patent, so no controversy existed.

Federal Circuit Conclusions

On appeal, the Federal circuit reversed the dismissal. The panel held that:

  • Daiichi’s disclaimer removed one, “but only one,” legal barrier to Apotex’s ability to enter the market. The legal stakes for the parties are high. If Apotex prevailed, it could (if the timing was right), enter the market without having to wait for Mylan’s exclusivity to run. Mylan, of course, could lose its exclusivity. And, Mylan’s exclusivity would also benefit Daiichi by minimizing price erosion during the exclusivity period.
  • The harm to Apotex (i.e., of having to wait for Mylan’s exclusivity to run) is traceable to Daiichi. Traceability is a constitutional requirement to press a legal action in the courts. Daiichi listed the patent in the Orange Book, and in so doing, Mylan and Daiichi get the potential benefit of the 180-day exclusivity.
  • Daiichi and Mylan argued that Apotex’s claim was speculative – because Apotex has apparently not yet received tentative approval, and may not get it in time. The panel rejects this out of hand. Tentative approval is never a requirement for a patent infringement action under the Hatch-Waxman scheme, because of the statutory infringement created by filing an ANDA with a PIV certification codified in 35 U.S.C. 271(e)(2).
  • Apotex’s strategy, if successful, can trigger the forfeiture. If Apotex gets tentative approval, which is possible prior to the expiry of the ‘599 patent, then the failure to market part (bb) comes into play. And if Apotex gets a final decision from which no appeal (other than a certiorari to the Supreme Court) has been or can be taken that the patent is invalid or not infringed, then (AA) is triggered, and a 75 day clock starts. If Mylan can’t launch within the 75 day period, the forfeiture event occurs and Mylan will lose its exclusivity. This could happen, for example, if Apotex gets tentative approval and a final decision earlier than 75 days before the expiry of the ‘599 patent, because Mylan can’t launch until the ‘599 patent expires.


This is a clever strategy by Apotex that plays into the hand of forces opposed to exclusivity. Generics may want to consider this strategy who are not first-to file-but who are not sued after filing of a PIV certification, to gain faster approval without having to wait for an exclusivity period to run.

I don’t have any great advice for Mylan in this case. Subjectively, it looks like they did as good a job as they could given the circumstances. Unfortunately for Mylan, they are on the wrong side of the fence with respect to the MMA amendments that have eroded the 180-day exclusivity benefit.

According to the docket at the N.D. of Illinois, this matter is back in the court. Apotex will probably oppose any deadline extensions in this case! Apotex must get this matter through the district court and up to the Federal Circuit on or before 76 days prior to the expiry of the ‘599 patent to trigger its forfeiture, so they need to rush at this point.

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Case Citation

Apotex Inc. v. Daiichi Sankyo, Inc., No. 2014-1282, 2014-1291 (Fed. Cir. 3/31/2015). Panel was Taranto, Mayer, Clevenger, opinion by Taranto.

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ATELVIA® Patents Obvious at District Court

03.15.15 Posted in District Court Opinions by

Judge Hochberg Finds Actavis’ ATELVIA® Patents Obvious

In a decision issued on March 4, 2015, Judge Faith Hochberg of the New Jersey District Court found two Warner Chilcott patents covering risedronate sodium delayed release tablets, US7645459 and US7645460, obvious in a Hatch-Waxman paragraph IV action against Teva Pharmaceuticals USA. Warner Chilcott is now owned by Actavis.

The patents describe 35 mg of risedronate sodium in combination with ethylene diamine tetraacetic acid (EDTA). The EDTA is said to chelate calcium in the digestive tract which can bind to bisphosphonates, such as risedronate, and prevent absorption of the drug in the gut when oral dosage forms are swallowed.

After Teva filed an abbreviated new drug application (ANDA) with a “Paragraph IV” certification, Warner sued Teva for patent infringement. Teva responded that the patents were anticipated or obvious. Teva primarily relied on a Brazilian patent application, published in 2003, which disclosed several bisphosphonate oral dosage forms in combination with EDTA.

With regard to the anticipation argument, the court found that all elements of the asserted claims were present in the Brazilian patent application except for a limitation of “pharmaceutically acceptable absorption” of the drug. The court concluded that under the clear and convincing standard required for a holding of anticipation, there was “insufficient evidence to clearly and convincingly find that any embodiment would necessarily produce the claimed element.” Slip op. at 25. Thus, the Brazilian application was not anticipatory.

However, in the obviousness prong, the court found that EDTA was a well known chelator of calcium, and that none of the secondary considerations reviewed by the court could save the patents. The court looked at teaching away, long-felt unmet need, unexpected results, simultaneous invention, skepticism, and failure of others.

In the analysis of the differences between the claims and the prior art, the key holding was in the discussion of “pharmaceutically acceptable absorption.” The court looked at whether the prior art suggested the claimed combination, and whether there was a reasonable expectation of success. Slip op. at 54. The court found that there was a motivation to improve the oral absorption of bisphosphonates, to use EDTA to bind calcium in the digestive tract, and to limit the amount of EDTA to spread tight junctions in the intestine (an undesirable outcome of high doses of EDTA). Slip op. at 58. The court also found there would be a reasonable expectation of success that EDTA would solve the problem. “A person of ordinary skill in the art would have had a reasonable expectation of success that a dose of EDTA could reliably chelate the expected amount of calcium in the small intestine after a meal without separating the tight junctions and substantially increasing absorption. The expected result of such a formulation would be ‘absorption [that] is similar with or without food.’” Slip op. at 61.

The court therefore found clear and convincing evidence that a person of ordinary skill at the time of the invention (in 2005) would have been motivated to use EDTA in the claimed amounts with a reasonable expectation of success. Slip op. 65–66.

The asserted claims were accordingly found to be obvious.

Citation: Warner Chilcott Co. LLC v. Teva Pharms. USA, Inc., No. 11-6936 (D.N.J. 3/4/2015)


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Entecavir Obvious?

03.06.15 Posted in Federal Circuit Opinions by

In this Hatch-Waxman case, Bristol-Myers Squibb, owner of the drug entecavir (sold as Baraclude®, indicated for hepatitis B (HBV) infection), sued Teva Pharmaceuticals for patent infringement. Teva responded that the patent (the only patent at issue was US5206244, priority date 10/18/1990), which claims the chemical structure of entecavir, was obvious. The district court found in favor of Teva. This finding was affirmed by the Federal Circuit panel. En banc review was denied.

The obviousness argument was that 2’-CDG was the lead compound, and that entecavir was merely a minor modification of 2’-CDG, termed a “small conservative change.”



Teva argued that 2’-CDG in turn is structurally similar to the natural nucleoside deoxyguanosine. Teva also argued that “Madhaven Compound 30,” a 2’-hydroxy analog of entecavir (and §102(b) prior art to the ‘244 patent) is the exo-methylene analog of aristeromycin. Madhaven compound 30 was said to have substantially improved antiviral properties as compared to aristeromycin.


The panel found no clear error in the district court findings that entecavir was obvious in view of:

  • Structural similarity between entecavir and 2’-CDG;
  • Teachings of Madhavan;
  • The exo-methylene substitution is a “small conservative change”; and
  • The totality of the prior art on 2’-CDG

The panel found that a skilled artisan would have been motivated to substitute an exocyclic methylene at the 5’ position of 2’-CDG with a reasonable expectation of success of creating a compound with beneficial antiviral properties.

The most significant feature of this case is the treatment of post-filed data. BMS argued that several features of entecavir were discovered after the ‘244 patent was filed in 1990, but the district court discounted these arguments, which were all upheld in Chen’s opinion finding entecavir obvious.

Thus, BMS challenged the selection of 2’-CDG as a lead compound because it was found to be toxic in the 1990’s, after the file date of the ‘244 patent. The panel dismisses this argument, asserting that obviousness is measured at the time of the invention, citing to Velander v. Garner, 348 F.3d 1359, 1377 (Fed. Cir. 2003). Likewise, Madhavan compound 30 was found to more toxic than aristeromycin after the ‘244 patent was filed, but again Chen asserts that the reasonable expectation of success provided by Madhavan is measured as of the date of the invention, citing to Amgen v. Roche, 580 F.3d 1340, 136 (Fed. Cir. 2009).

BMS also argued that post-filed data supported its arguments that secondary considerations rebutted the prima facie case of obviousness. BMS argued that entecavir had the unexpected properties of (1) high potency against hepatitis B, (2) a larger than expected therapeutic window, and (3) a high genetic barrier to resistance. All of these features were discovered after the ‘244 patent was filed, but Chen agreed with the District Court that entecavir was expected to have some antiviral activity based on the similarity to 2’-CDG, and Chen asserted that these unexpected properties were merely differences in degree.

However, Judge Newman’s dissent forcefully argues the panel disregarded the long established practice that comparative post-filng data can be used to rebut a prima facie case of obviousness and can be used to show a new property or use unexpected in light of the prior art. 769 F.3d at 1347-1348.

BMS also argued that a new chemical entity cannot be obvious as a matter of law if unexpected properties are demonstrated. Chen dismisses this argument, holding that an unexpected result or property does not by itself support a finding of non-obviousness, 752 F.3d at 977, citing to In re Dillon, 919 F.2d  , 693, 697 (Fed. Cir. 1990). Judge Taranto responded to this argument in his dissent to the denial of en banc review, arguing that the panel took the statement from Dillon out of context. 769 F.3d at 1354. Tarranto argues that in the reasonable expectation of success prong, the panel erred by not considering “particular unexpected results” pertaining to efficacy and safety. This argument again comes down the matter of whether post-filed data is relevant to the obviousness analysis.

Tarranto also argues that the issue decided in Dillon was only what was needed to establish a finding of prima facie obviousness, not what could properly rebut a finding of obviousness. Finally, Tarranto argues that the panel should not have ruled on the doctrinal relationship between a finding of unexpected results and a finding of the prima facie case elements, because the panel concluded (even if erroneously) that there were no appreciable unexpected results.

Judge Dyk’s concurrence with the denial of en banc review agreed with the panel that the post-filed data was properly excluded.

Judge O’Malley concurred with the denial of en banc review, writing to assuage fears that this decision rewrites the test for obviousness in pharmaceutical patents, and asserting that the standard is unchanged. O’Malley argued that the post-filed data was properly considered but doesn’t save BMS. However, O’Malley also suggested that BMS raised evidence of entecavir’s unexpected properties and reasonable expectation of success (presumably its HBV activity) as “an afterthought” in its opening brief.

Comment: while this case seemingly tips the scales strongly in favor of generics, caution should be exercised in reading too much into this holding. This case appears to be the first time the Federal Circuit found a novel pharmaceutical compound invalid as obvious on a full review,[1] based on structural similarities in the prior art with a “lead compound” analysis. A number of previous compounds were all found to be not obvious, including rosuvustatin, pregabalin, olmestartan, aripiprazole, rabeprazole, and pioglitazone. So the question is, will the Federal Circuit start finding other compound patents invalid routinely?

The panel did not address the commonly applied principle that the chemical and pharmaceutical arts are inherently unpredictable (Eisai Co. Ltd., et al. v. Dr. Reddy’s Laboratories, Ltd., et al. 533 F.3d 1353, 1359 (Fed. Cir. 2008)), an omission that cuts in favor of the innovators.

Also, the split panel in the en banc review (6-4) (Prost did not participate in the decision to deny en banc review) does not give the victor here a clean win.

But for generics, this case suggests that in future arguments along these lines, generic challengers should stick to arguments that post-filed data is of limited probative value. Generic challengers should also emphasize that modifications to a lead compound are minor, and result in predictable changes in activity. Generic challengers should seek to exclude later filed data using this case as precedent, arguing that obviousness should be determined at time of invention or filing.

This case may call into question the paradigm of the lead compound analysis. It may be difficult to argue going forward that any chemical modification to a lead compound is anything but a “small conservative change.” However, this concern should be coupled with whether chemical and pharmaceutical arts are predictable. If chemical and pharmaceutical arts really are unpredictable, a small conservative change will not have a predictable effect. So a new procedure may be needed to evaluate the obviousness of chemical structures.

Case citation: Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967 (Fed. Cir. 2014); Judges Prost, Plager, and Chen; Opinion by Chen. En banc review denied, 769 F.3d 1339 (Fed. Cir. 10/20/2014); concurring in the denial were opinions by Dyk and O’Malley; dissenting from the denial of review were opinions by Newman and Taranto.

[1] But in Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999 (Fed. Cir. 2009), pantoprazole was held to be obvious on a motion for a preliminary injunction, i.e., a likelihood of success standard.


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Megestrol Nanoparticle Formulation Claims – Not Inherently Obvious (at least not yet)

12.19.14 Posted in Federal Circuit Opinions by

Contact the author: Andrew Berks

Case citation: Par Pharmaceutical Inc. v. TWi Pharmaceuticals, Inc., No. 2014-1391 (Fed. Cir. 12/3/2014) (O’Malley, Wallach, Hughes, opinion by O’Malley)

In this dispute, Par is in the role of innovator drug company—they make a product called “Megace ES” which is a nanoparticle formulation of megestrol acetate, a drug useful for treating cachexia (wasting syndrome) in AIDS patients. A prior formulation, Megace OS, is micronized. Megace ES is asserted to have the critical advantage over the micronized formulation of much less variability in bioavailability based on whether the patient had a recent meal. Par has an Orange Book-listed patent on Megace ES, US7101576, at issue in this case.

TWi filed an Abbreviated New Drug Application (ANDA) with a paragraph IV certification alleging the claims of the ‘576 patent were invalid. This decision only considered the obviousness arguments. The claim discussed in the opinion recites a method of increasing body mass in a patient suffering from anorexia, cachexia, or loss of body mass, with a nanoparticle megestrol formulation wherein there is no significant difference in the Cmax (maximum blood concentration of the drug) with regard to the fed/fasted state of the patient.

The district court found the claims obvious based on an inherent obviousness argument. The Federal Circuit panel vacated and remanded, objecting to the inherency arguments.

In the summary of the district court holdings, TWi showed that megestrol was known to have poor bioavailability, but failed to prove that Megace OS had a known bioavailability problem or a known food effect in the prior art. The court concluded that TWi proved that all elements of the claimed invention were disclosed in the prior art. However, with regard to the food effect limitation of the claim, of bioavailability based on the whether the subject had a recent meal, the prior art did not explicitly disclose the food effect as claimed. The district court agreed with TWi that the  reduced food effect of Megace ES was “an inherent result” of nanosized megestrol, even if it was previously not known in the prior art that a food effect existed. Slip op. at 9–10. The district court also found that Par had a motivation to combine references disclosing bioavailability of megestrol and nanoparticle drug formulations. The district court also found that objective indicia of obviousness, including evidence of unexpected results and long-felt need, did not overcome the obviousness arguments.

In the analysis of the substantive obviousness arguments, the Federal Circuit panel says the parties agreed that all limitations of the claim were disclosed in various prior art references, except the specific food effect limitation. But with regard to TWi’s argument that the food effects are an inherent property of the formulation disclosed by an obvious combination of prior art elements, the panel was very concerned about the application of an inherency analysis in the obviousness context. Inherency is rooted in the law of anticipation and the opinion says its application to obviousness “must be carefully circumscribed.” Slip op. at 14. Inherency has been recognized previously as supplying missing claim limitations in the obviousness context. Id. However, in an obviousness analysis, an inherency argument has a heightened standard that must be the natural result flowing from the operation as disclosed in prior art references. Slip op. at 15. The panel concludes that the district court relied on  probabilities or possibilities to find the claims inherently obviousness, and therefore failed to meet this burden.

The panel also found that the district court did not require TWi to present evidence to prove inherency to the heightened obviousness standard, so the panel vacated the district court’s inherency analysis and remanded for the district court to determine whether TWi has clear and convincing evidence that the food effect as claimed is necessarily present in the prior art formulation. Slip op. at 17.

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Means-plus-function claims – indefinite because of insufficient structure in the specification

10.27.14 Posted in Federal Circuit Opinions by

Contact the author: Andrew Berks

Robert Bosch, LLC v. Snap-On, Inc., No. 2014-1040 (Fed. Cir. 10/14/2014).

The Federal Circuit panel, (Prost, Taranto, and Hughes) outlines a two-step framework for determining if a claim invokes 35 U.S.C. § 112(f) (formerly (formerly 112 ¶ 6). The panel concludes the challenged claim invoked 35 U.S.C. § 112(f), i.e., the claim is a means-plus-function (MPF) claim. The court then concluded that the challenged claim was indefinite.

First, a claim is presumed drafted in a means-plus-function format if it contains the word “means,” Bosch at 4, citing EnOcean GmbH v. Face Int’l Corp., 742 F.3d 955, 958 (Fed. Cir. 2014). However, the word “means” is not mandatory to trigger this presumption if the claim term fails to recite sufficiently definite structure or else recites function without reciting sufficient structure for performing that function. Id., quotes omitted.

Second, the court should construe the disputed claim term by identifying the corresponding structure, material, or acts described in the specification to which the claim term will be limited. Bosch at 5, citing Welker Bearing Co. v. PHD, Inc., 550 F.3d 1090, 1097 (Fed. Cir. 2008).

If the court is unable to identify any corresponding structure, material, or acts described in the specification, the claim term is indefinite. Bosch at 5, citing Noah Sys., Inc. v. Intuit Inc., 675 F.3d 1302, 1312 (Fed. Cir. 2012).

Holdings: In Bosch,

a.  The disputed claim was not presumed to be an MPF claim, even though the word “means” is in the claim.

b.  However, the court nevertheless construes the disputed claim as an MPF claim.  The disputed claim did not overcome the presumption against concluding that the claim as an MPF claim, because the claim language did not recite sufficient structure to avoid § 112(f), so the court concludes the claim invokes § 112(f).

c.   The panel then concludes that the claim terms “program recognition device” and “program loading device” were indefinite, because there was no guidance in the specification about structures corresponding to these claims terms. Further, since these terms are found in the only independent claim of the ’313 patent, all claims in the ’313 patent are invalid.

Andrew Berks 10/27/2014

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