Tag Archives: Obviousness

SCHRÖDINGER’S POLYMORPH: WHEN A CRYSTALLINE FORM CLAIM IS OBVIOUS AND INVALID

Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc., No. 22-2153 (Fed. Cir. 2024)

“Schrödinger’s cat,” is a paradoxical thought experiment devised by physicist Erwin Schrödinger, while debating quantum superposition in 1935. Oversimplified, in the thought experiment, there is a cat in a box, and you have no way of knowing what physical state the cat is in, like a quantum wave function, until you open the box and observe it.

While studying polymorphic forms, like Schrödinger’s hypothetical [albeit a long stretch], you do not know what form a solid compound is until you measure it with x-ray crystallography. However, unlike Schrödinger’s hypothetical, you may have a reasonable expectation of succeeding to figure out what form your compound is depending on the prior art and knowledge of a person of ordinary skill.

Shifting from quantum to organic chemistry patent law, if there is a reasonable expectation of success in characterizing a known crystalline product for potential polymorphism using routine, conventional methods and skill, then a claim to that crystalline product would be invalid for obviousness. Such was the decision in Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc., No. 22-2153 (Fed. Cir. 2024).

Salix claimed a specific crystalline form (form β) of rifaximin. The United States patent and Trademark Office (USPTO) granted Salix a patent on it.  However, when litigated, the United States Court of Appeals for the Federal Circuit (CAFC) affirmed the District Court of Delaware’s finding that Salix’s claims to rifaximin form β were invalid for obviousness.*

“The difference between the prior art and the claims is thus effectively nothing more than the performance of routine characterization to identify the polymorphic forms that result from the known Cannata processes.”

Salix Pharmaceuticals, Ltd. v. Norwich Pharmaceuticals Inc., No. 22-2153 (Fed. Cir. 2024), at 15.

In other words, you cannot claim ownership of a compound just by making the expected crystalline form using someone else’s process and taking an x-ray crystal structure of it and giving a Greek letter name.

Background

  • Salix markets Xifaxan® (rifaximin), and Norwich wanted to sell a generic version.
  • Xifaxan® is a formulation of rifaximin crystalline form β.
    • Polymorph β is a commonly produced polymorph.
    • Polymorph β the most stable form of rifaximin.
  • Disputed patent claims: Claim 4 of U.S. Patent No. 7,612,199 and Claim 36 of U.S. Patent No. 7,902,206.
    • Claim 4. Rifaximin in polymorphic form β, wherein the rifaximin has x-ray powder diffraction pattern peaks at about 5.4°; 9.0°; and 20.9°2θ and wherein the rifaximin has a water content of greater than 5%.
  • Prior art: Cannata et al. U.S. Patent No. 4,557,866.
    • Although Cannata does not discuss rifaximin’s crystal structure in detail, it does disclose several preparation protocols for rifaximin that include solvents used for crystallization.
    • Experts testified that Cannata’s preparation of crystalline Rifaximin would have yielded its β form. But they could not say it would every time.
  • Rifaximin was a known compound with a known, useful activity (antibiotic).
    • While rifaximin was a known antibiotic, Salix owns rights to patents covering new method of use (hepatic encephalopathy). Salix won on appeal for such method-of-use claims.
  • Experts testified that Cannata’s preparation of crystalline rifaximin would have easily made and taken an X-Ray diffraction pattern to determine that rifaximin was in its β form.
    • The experts could not convince the judge that the prior art process would produce rifaximin form β “every time.” If they could, then Salix’s claims would have been anticipated (not novel) as inherently present in the prior art.‡
    • Although the experts could not convince the judge of the certainty of form β (novelty), they at least convinced the judge that form β was reasonably expected (obviousness).

    CAFC Opinion Discussion

    The CAFC decided that “the district court found a reasonable expectation of success in characterizing the crystalline product of Cannata for potential polymorphism using routine, conventional methods and skill [Salix Pharm., Ltd. v. Norwich Pharm., Inc., Civil Action No. 20-cv-430-RGA, (D. Del. Apr. 29, 2021), at *6–7].†  We see no clear error in that conclusion. Indeed, Salix has done no more than combine known elements of the prior art to verify readily accessible information concerning a compound already in the hands of those of ordinary skill in the art, and such routine efforts do not justify removing this polymorph from the public domain. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 427 (2007); see also Pfizer, 480 F.3d at 1367−68.”

    The District Court supported its factual determinations of obviousness with expert testimony that:

    (1)  a skilled artisan would have had good reason to characterize the crystalline rifaximin obtained by following the Cannata protocols,

    (2)  such characterization was routine and could have been performed “in one day,” and

    (3)  doing so would have led the skilled artisan to have “detected rifaximin β.” 

    Salix argued that a person of ordinary skill in the art would not have “expect[ed] to succeed” because, as of the critical date, the polymorphic nature of rifaximin had not yet been reported and the identity of the β form remained undisclosed. They further argue that a skilled artisan would not have been able to predict which polymorphic form Cannata made. This argument was flawed. The CAFC states that Salix’s is incorrect in framing of the issue, as it suggests that no unknown entity could ever be obvious, as one cannot reasonably expect what was hitherto unknown.

    * In the same appeal, The CAFC did affirm the District Court’s finding that Salix’s other claims to methods of treating hepatic encephalopathy were valid and nonobvious.

    † Whether or not there would have been a reasonable expectation of success is a question of fact. “Whether or not there would have been a reasonable expectation of success is a question of fact, (IXI IP, LLC v. Samsung Elecs. Co., 903 F.3d 1257, 1262 (Fed. Cir. 2018)), which we review for clear error, Hospira, 946 F.3d at 1328. We review the ultimate conclusion of obviousness de novo.” Did the Justices themselves believe that the claims were obvious? Unknown. The CAFC perhaps equivocated or sidestepped the question. The justices did not say that they themselves believe that the polymorph claims were obvious. Rather, they merely said that they found no clear error in the District Court’s finding of obviousness. 

    ‡ The CAFC did not opine on whether or not the polymorph claims were invalid for being inherently anticipated (§102). The court said that they did not need to go that far since they already determined that the claims were invalid for obviousness (§103). The district court said that the polymorph claims were not anticipated as being inherent because Norwich did not prove with clear and convincing evidence that the prior art method would produce rifaximin form β “every time.” The inherency issue may deserve its own post. Question for discussion: Does the “every time” requirement go too high for “clear and “convincing evidence?” Perhaps requiring a specific result Every time may go up to the realm of “beyond a reasonable doubt,” which is not the level of burden of proof for patent law. Recall last year’s discussion of the Amgen case where there were arguments about how many examples enable the “full scope” of a claim. Stay tuned.

    Additional Information

    OrganicPatents.com page on Obviousness of Stereoisomers &Purified Compounds

    Obviousness of Stereoisomers & Purified Compounds

    See also PatentDocs’s post: https://www.jdsupra.com/legalnews/salix-pharmaceuticals-ltd-v-norwich-3362384/.


    May 8, 2024

    Inherency & Therapeutic Mechanisms: Reviewing In re Couvaras – (With No-Frills Diagrams)

    Q:  When can you patent a composition’s mechanism of action?

    A:  When the mechanism is not inherent in a known use of the composition.

    “Reciting the mechanism for known compounds to yield a known result cannot overcome a prima facie case of obviousness, even if the nature of that mechanism is unexpected.”

    In re Couvaras, 22-1489 (Fed. Cir., 2023)

    In re Couvaras, 22-1489, 2023 WL 3984753 (Fed. Cir., June 14, 2023)

    Precedential Opinion by Circuit Judge Lourie; joined by Circuit Judges Lourie, Dyk, and Stoll

    The United States Court of Appeals for the Federal Circuit (CAFC) agreed with the Patent Trial & Appeals Board (PTAB), and the USPTO examiner, that claims in U.S. Patent Application No. 15/131,442 (US2016/228,393), which recites methods of increasing prostacyclin release in the systemic blood vessels of a human with essential hypertension to improve vasodilation, were obvious because the claims relate to combatting hypertension with known antihypertensive agents and merely disclose their previously unappreciated mechanism of action.”

    High Level Summary

    The prior art taught that GABA-a agonists and ARBs reduce anti-hypertension. Dr. Couvaras discovered that GABA-a agonists and ARBs reduce anti-hypertension, in part, because they increase prostacyclin and promote vasodilation. Dr. Couvaras applied for a patent claiming a method of increasing prostacyclin in an individual with hypertension to improve vasodilation by providing an ARB and a GABA-a agonist.  However, the USPTO rejected the claims because the element of increasing prostacyclin was inherent in the well-known prior art method of independently treating hypertension with an ARB or a GABA-a agonist. 

    Visualizing the case with diagrams

    Now let’s skeletonize the elements of this case down to arrow diagrams. We don’t need too many facts getting in the way of this good story. 🙂 *

    Claim 11 (abridged): A method of increasing prostacyclin in an individual with hypertension to improve vasodilation by providing an ARB and a GABA-a agonist. 

    A = Providing an ARB and a GABA-a agonist 

    X = Increasing prostacyclin

    B = Vasodilation (treating hypertension)

    * But seriously, although I am scientist reluctant to loose any nuance, technical terms such as Angiotensin II Receptor Blocker (“ARB”) can be distracting in analyzing the the law in case.  Also, I believe that knowing the claims recite a combination therapy is superfluous and thereby distracting itself. (At least I found them distracting at first. Maybe that’s just me. Please work with me for now.) The CAFC’s rule of law works for both mono and combo therapies. See below for a discussion regarding combination therapies.

    The overall goal is to get from A to B. Doctors already know how to get from A to B. It is prior art. No argument there. Then an inventor discovers that X is the mechanism of action that leads to B.

    Doctors did not already know that going from A to B involves X. This is not taught in the prior art.  A→X is a genuine new discovery. No argument there either.

    Now you have  A→ X→ B.

    Although the discovery of A→ X is indeed new, inventors should not be able to patent a claim to the discovery. Even though doctors did not know it, doctors were inherently doing the process of A→ X→ B by simply prescribing A to treat B.  It makes sense that someone should not be able to patent a claim to  A→ X→ B, or even simply A→X, then suddenly prevent doctors from prescribing A→ B, which they have been doing all along.

    New methods and mechanisms of action may still be patented

    In re Couvaras, however, does not mean that all mechanisms and new uses are not patentable. New uses for old compounds May still be patentable. For example, an inventor may discover that A also renders the benefit of C, and that A affects B by going through mechanism Y.

    In this example, the inventor may be able to patent a claim to A→C.

    If an inventor simultaneously discovers that A→C goes through the mechanism “Y” then they may be able to patent a claim covering both A→C, A→Y,  and A→Y→C.  

    NOTE: The inventor should file both claims simultaneously so the inventor’s disclosure of A→C does not block the claim to A→Y. If not, then the inventor will have the same problem from In re Couvaras.

    In summary, patentability of mechanisms (X/Y) rest on the whether the overall benefit (B/C) is unexpected from the known composition (A).

    Secondary Considerations

    Of course, secondary considerations provide some leniency. But the secondary considerations surely need to be compelling.

    “To establish unexpected results, Couvaras would have needed to show that the co-administration of GABA-s agonist and an ARB provided an unexpected benefit,” such as, e.g., better control of hypertension or less toxicity.

    Failure of others: “The purported failure to achieve prostacyclin increase through pursuing an unrelated goal did not establish the non-obviousness of the claimed method.”

    No long felt need: The anti-hypertensive agents were admitted to be available already.

    “The pending claims of the ’422 application literally recite methods of increasing prostacyclin release in the systemic blood vessels of a human with essential hypertension to improve vasodilation. That increased prostacyclin release is achieved by co-administering two well-known types of antihypertensive agents: a GABA-a agonist and an Angiotensin II Receptor Blocker (“ARB”). In reality, the claims relate to combatting hypertension with known antihypertensive agents and claiming their previously unappreciated mechanism of action.”

    Novelty vs. Obviousness: Inherency

    Q: Why is inherency in a case about obviousness and not about novelty?

    A: Here is where the combo-therapy aspect comes in. A combination of two known compounds that render the same benefit is obvious. Dr. Couvaras argued that the discovery of the compounds’ mechanism of action overcame the obviousness rejection. Essentially the argument tried to convince the examiner that each mono therapy was novel. With two novel monotherapies in hand, reasoning follows that combination of two novel monotherapies would have been non-obvious.

    Post Script

    On bright side, The USPTO awarded Dr. Couvaras with U.S. Patent No. 9,339,542 in his earlier application. Composition claims to combinations were non-obvious.

    Granted Claim 1:  A composition effective to relax Smooth muscles in an individual in an altered state, the composition comprising: a dosage of GABA or GABA-a analogue; and a dosage of at least one of an ACE inhibitor and a ARB combined with the dosage of GABA or GABA-a analogue into a deliverable form.

    Amgen Throws Patent Attorneys Under Bus

    “Chemists would not routinely rely on the statements of patent lawyers.”

    Amgen v. Sandoz, 22-1147 (CAFC, 2023)

    Please pardon my delay in posting. I needed to check my wall to see if my diploma was still hanging there. Yes, it is still there. Like many of my fellow patent attorneys, I have a PhD in chemistry. Being a patent attorney and a chemist is not mutually exclusive. To be fair, my laboratory technique might be quite rusty after 20 years behind a desk. But I still consider myself 100% a chemist.

    Twice, Amgen’s litigators successfully argued that Amgen’s own patent prosecutors were wrong and should be ignored. First, Amgen persuaded the court to ignore disclosure in the patent application specification regarding purification processes using crystallization. Second, Amgen persuaded the court to ignore statements that their European Council made to the European Patent Office (EPO) regarding which products resulting from Example 2 of Amgen’s U.S. Provisional Application 60/366,515.

    Patent attorneys often worry about potential adverse statements that anybody makes during prosecution of patent applications. Keep statements and arguments minimal because, once in writing, you cannot take them back. This case appears to be a rare exception. Depending on whose side you’re on, perhaps it is refreshing that cases such as this show that potentially detrimental statements may be ignored once in a while provided the right evidence.

    Otezla® (apremilast) ANDA litigation

    Background

    Apremalist is an optically pure dextrorotary “(+)” enantiomer of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, having its
    stereo center in the “S” conformation. Stereoisomers regarding apremalist are a big deal because of their similarities to thalidomide.

    The dispute arose from Sandoz’s filing an Abbreviated New Drug Application (ANDA) to sell a generic version of Amgen’s Otezla® (apremalist), a PDE-4 inhibitor used for treating psoriasis.

    Amgen then sued Sandoz to enforce, among others, U S. Patent 7,427,638 claiming a pharmaceutical composition comprising the (+) enantiomer, and U.S. Patent 10,092,541 claims a crystalline solid form of the (+) enantiomer (Form B).

    There were several other issues in this opinion. One that I have spent much time considering is the issue of patenting of stereoisomers.  Look out for my subsequent post to the page “Obviousness of Stereoisomers & Purified Compounds” regarding the decision in this case.

    Priority Claim

    U S. Patent 7,893,101 claims priority to earlier provisional patent application 60/366,515. Sandoz argued that the priority claim was invalid because Example 2 in the provisional application, instead of making only crystalline Form B, also made Form C. Sandoz cited as evidence Amgen patent council’s statements to the EPO stating that Example 2 made both forms. However, counsel’s statement was wrong because Example 2 indeed only made Form B. Amgen was allowed to present data to prove it, including thirteen third-party experiments. With the data as evidence, Amgen was able to take back their erroneous, detrimental statement.

    Non-Obviousness

    Sandoz argued that Amgen’s claims to optically pure compound were obvious because statements in the specification about the separation of the enantiomers. The Statements made the process of isolating enantiomers sound routine. However, Amgen was able to persuade the court that isolating the (+) enantiomer was not routine because, contrary to the specification, formation of chiral salts was not viable. In other words, oversimplified colloquially, the patent attorney drafting the application made the invention sound too easy describing techniques that real chemists would know actually would not work.

    Stereogenic Oxygen!

    I have been updating my page on patentability / non-obviousness of chiral compounds. While working on it, I read about a new molecule ─ a chiral triaryloxonium ion ─ in Chemical & Engineering News (C&EN). Astoundingly, the stereocenter is the oxygen, rather than a carbon, the atom most famous for its chiral capabilities. Chemists synthesized the first stable molecule whose chirality is solely attributed to a stereogenic oxygen. They published their work in Nature. See, O. Smith et al., Control of Stereogenic Oxygen in a Helically Chiral Oxonium Ion, Nature, 615, 430–435 (2023). 

    Link to C&EN article: This New Molecule Owes its Chirality to Oxygen Alone

    Can someone patent a chiral oxonium ion?

    We do not know if the chemists filed a patent application claiming the composition. But that didn’t stop me from speculating as to such a possibility. I think that a patent application claiming a chiral oxygen would be robust. Firstly, the inventors reduced the molecule to practice. They physically made it. It surely is not an abstract idea. Secondly, if the molecule is truly the first stable molecule, then novelty should be no problem. Thirdly, I think that such a compound is non-obvious and inventive.

    Might a chiral oxygen be obvious?

    Let’s focus on non-obviousness. Might a chiral oxonium ion be obvious? I think that, most likely, a chiral oxonium ion would not be obvious. As noted on Organic Patent’s page, Obviousness of Stereoisomers & Purified Compounds, critical support for arguing non-obviousness includes evidence of unexpected properties and difficulties associated with resolving compounds. Other secondary considerations / “Graham” factors are super helpful too, such as long felt but unsolved needs. The articles cited above have an abundance of such evidence.

    Below are a few powerful quotes:

    • “Oxygen has been less cooperative.”
    • “Oxonium ions … have the potential to be chiral, but they are notoriously reactive”
    • “The few previous examples of chiral oxonium ions are too unstable to be isolated … so the search for chiral oxonium ions languished in the literature”

    Pemetrexed (ALIMTA®) Patent Survives an IPR Obviousness Challenge

    December 12, 2017

    Eli Lilly’s patent (US Patent No. 7,772,209 claiming methods for administering pemetrexed) survived an IPR Challenge on obviousness (IPR2016-00237).

    Recall back in January, the patent made headlines when Eli Lilly won in court with an opinion that Teva was liable for induced infringement of the patent’s methods of administering pemetrexed.

    Teva Liable for Induced Infringement of Eli Lilly’s Methods of Administering Pemetrexed (ALIMTA®)

     

     

    Onglyza® and Kombiglyze® XR (saxagliptin) Patent Survives Challenge from Mylan

    September 12, 2017

    Mylan and other generic manufacturers petitioned the Patent Trial and Appeal Board (PTAB) to institute an inter partes review of AstraZeneca’s patent claiming compositions including saxagliptin. AstraZeneca markets saxagliptin as Onglyza® and Kombiglyze® XR for diabetes.

    Case IPR2015-01340 / Patent RE44,186 E

    The PTAB’s Administrative Patent Judges (APJ) decided that the petitioners did not show with preponderance of the evidence that the claims of Reissue RE44,186 of U.S. Patent No. 6,395,767 would have been obvious to a skilled artisan.  Particularly, saxagliptin was not obvious over “compound 25.”

    Saxagliptin:

    Saxagliptin Structure

    Saxagliptin Structure

    Prior art: “Compound 25”

    Structure of Prior Art "Compound-25"

    Structure of “Compound-25”

    State of the Art:

    Experienced medicinal chemists (Persons of Ordinary Skill in the Art [PHOSITA]) knew saxagliptin bound to DP 4.  But they did not have detailed knowledge of DP 4’s active site for guidance in designing inhibitors because DP 4’s crystalline structure was unknown. At the time of invention, knowledge of DP 4’s binding requirements came from structure-activity relationship (“SAR”) studies.

    Lead Compound Analysis:

    Petitioners cited a publication by Ashworth containing Compound-25, which they argued would have been selected as a lead compound. (Ashworth et al., 2-“Cyanopyrrolidides as Potent, Stable Inhibitors of Dipeptidyl Peptidase IV,” 6(10) Bioorganic &Med. Chem. Lett., 1163–66 (1996)).

    “Compound-25” would not have been selected as a lead compound

    The PTAB reasoned that a medicinal chemist would not have selected compound 25 as a lead compound because, among other reasons, (i) Compound 25 was only one of several other similar compounds (ii) Compound 25 only had in vitro data obtained using non-physiological conditions, (ii) there were two much more advanced compounds in clinical trials (i.e., NVP-DPP728 & P32/98) and (iii) Ashworth’s subsequent publication focused on different series of compounds.

    NVP-DPP728 & P32/98

    Clinical Compounds NVP-DPP728 & P32/98

    The PTAB’s analysis could have ended there. But even accepting Petitioners’ assertion that a skilled artisan would have chosen compound 25 as a lead compound, the PTAB determined that the Petitioners didn’t demonstrate that a skilled artisan would have had reason to modify compound 25 with a reasonable expectation of success to arrive at the claimed saxagliptin.

    Check out PatentDocs’s Post for further discussion:

    http://www.patentdocs.org/2017/09/mylan-pharm-v-astrazeneca-ab-ptab-2017.html

     

     

    Velcade® Patent Validated by CAFC

    August 8, 2017

    Millennium Pharmaceuticals, Inc. v. Sandoz Inc. (Fed. Cir. 2017)

    A Court of Appeals for the Federal Circuit (CAFC) panel reversed the district court’s holding that Millennium’s licensed patent, U.S. Patent No. 6,713,446 (“the ‘446 Patent”) was invalid for being obvious. The ‘446 Patent claimed a lyophilized mannitol ester prodrug of Bortezomib (See Claim 20). Claim 20 was not obvious according to the panel because, among other reasons, the inventors unexpectedly “discovered that the reason for the dramatic improvement in dissolution and stability for this formulation was the formation of a new chemical compound during lyophilization: the claimed ester of bortezomib and mannitol.”

    • Claim 20:  The lyophilized compound D-mannitol N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

    Earlier, the district court concluded that the new compound was obvious reasoning that Bortezomib was already known (U.S. Patent No. 5,780,454), Lyophilization is already known known, and that the claimed compound is “the inherent result of an allegedly obvious process” of  lyophilizing bortezomib and mannitol together.

    • There was no evidence that anyone “foresaw, or expected, or would have intended, the reaction between bortezomib and mannitol, or that the resulting ester would have the long-sought properties and advantages”
    • “The district court did not find that the prior art taught or suggested that the claimed new compound would be formed, or taught or suggested making the claimed new compound by any method, or taught or suggested that this new compound would have the properties of stability, solubility, and dissociability that it exhibited.”
    • “No reference taught or suggested reacting bortezomib with mannitol, and no reference hinted that such an esterification reaction might occur during lyophilization.”
    • “No reference taught or suggested that the product of such lyophilization would be a new chemical compound that would solve the problems that had inhibited development of bortezomib in oncology.”
    IP Watchdog Post by Jay Pattumudi:
    http://www.ipwatchdog.com/2017/08/10/inherent-obviousness-motivation-modify-lead-compound-surprising-unexpected-results/id=86661/
    Patent Docs Post:
    http://www.patentdocs.org/2017/07/millennium-pharmaceuticals-inc-v-sandoz-inc-fed-cir-2017.html
    Dilworth IP Post:
    http://www.dilworthip.com/nonobviousness-push-back-millennium-pharma-v-sandoz/
    VELCADE® Prescribing Information:
    http://www.velcade.com/Files/PDFs/VELCADE_PRESCRIBING_INFORMATION.pdf
    VELCADE® (bortezomib) Official Website:
    http://www.velcade.com/

    STIVARGA® (regorafenib) Survives Challenge at PTAB: Difference = One Fluorine

    February 8, 2017

    FUSTIBAL LLC (Petitioner)  v. BAYER HEALTHCARE LLC, (Patent Owner)

    Case IPR2016-01490
    Patent 8,637,553 B2

    Link to PTAB Decision Denying Institution

    ——————————————
    Regorafenib (API of STIVARGA®)
    Regorafenib.svg
    ——————————————
    Prior art compound = Sorafenib (Nexavar®)
    Sorafenib structure
    ——————————————

    Summary

    The Patent Trial and Appeal Board (PTAB) declined Fustibal’s petition to Institute an Inter Partes Review (IPR) trial of Bayer’s U.S. Patent 8,637,553 B2 claiming regorafenib (API of STIVARGA®).

    The PTAB concluded that Fustibal did not establish a reasonable likelihood that Bayer’s claims are rendered as anticipated or obvious by the prior art.

    At first glance, Fustibal’s petition looks strong because Bayer’s regorafenib merely differs from the prior art’s sorafenib by one fluorine on the center aromatic ring.  [Sorafenib does not have the extra fluorine] Fustibal argues that Bayer merely added fluorine as an obvious modification.

    Fustibal challenged both regorafenib’s novelty and non-obviousness over the closest prior art publication WO 00/42012 to Riedl.

    PTAB’s Deference to the Patent Examiner

    The PTAB declined to second-guess the Patent Examiner because the examiner repeatedly reconsidered the prior art patent (Riedl) during prosecution and expressly allowed the claims over the prior art.

    The patent examiner provided the following Reasons for Allowance:

    “After a thorough search, the closest prior art, WO 00/42012 to Riedl, et al. was found to teach similar phenyl-urea derivatives as kinase inhibitors.  However, the WO document fails to teach or render obvious the instant claimed compounds according to Formula (I), and does not fairly suggest their salts or pharmaceutical compositions.”

    The PTAB further declined to institute an IPR trial on the merits.

    Anticipation / Novelty – §102

    Even though the prior art recited a genus that would encompass regorafenib, the PTAB determined that the prior art genus was too vast to anticipate regorafenib.

    • Where “the number of compounds actually disclosed by [the asserted prior art] numbers in the millions (including all proposed alternative substituents),” the prior art genus cannot anticipate a later species claim.  (Eli Lilly & Co. v. Zenith Goldline Pharm., Inc., 471 F.3d 1369, 1376 (Fed. Cir. 2006))
    • Where a reference does not “clearly and unequivocally disclose the claimed compound,” to be anticipatory reference under 35 U.S.C. § 102, it must, nevertheless, “direct those skilled in the art to the compound without any need for picking, choosing, and combining various disclosures not directly related to each other by the teachings of the cited reference.”  In re Arkley, 455 F.2d 586, 587 (CCPA 1972).  For the reasons set forth at pages 9–16 of the Preliminarily Response, we agree with Patent Owner that the genus relied on by Petitioner, having “‘eight individual chemical compounds possible when substituting a halogen”—F, Cl, Br, or I—at position 2/2’ or 3/3’ of the central ring of sorafenib, does not exist in Riedl, and only results from Petitioner’s improper picking and choosing disparate aspects of the disclosure.  See Prelim. Resp. 13–15 (quoting Pet. 16).

    Obviousness – § 103

    As expected, the PTAB applied the two-prong inquiry [“lead compound analysis”] from Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291–93 (Fed. Cir. 2012) for determining whether a claimed compound would have been obvious over prior art compounds.  First, the PTAB determined whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or starting points, for further development efforts.  Second, the PTAB analyzed whether there was a reason to modify a lead compound to make the claimed compound with a reasonable expectation of success.

    The PTAB noted that Fustibal’s petition did not include a “mandatory” lead compound analysis.  Fustibal merely assumed – without explanation – that a person of ordinary skill in the art would select sorafenib as a lead compound for modification.

    The PTAB did not discern a reason to select from Sorafenib from the prior art Riedl reference because the reference does not highlight any of the vast number of disclosed compounds is having particularly beneficial properties or present any enzymatic or biological data.

    No reason to modify Sorafenib by adding one fluorine to arrive at Regorafenib

    Fustibal’s petition did not provide the necessary reasons why a chemist would modify the prior art in that particular manner. Even though the prior art discloses potential benefits of adding one or more fluorine atoms, the prior art merely indicates that the prior art compound can be halogenated.

    The PTAB did not read the prior art to suggest that any fluorine substitution will result in improved pharmacological properties.  The PTAB agreed with the patent owner that if improvements by adding fluorine were always true, then “all pharmaceutical compounds would be fluorinated, which is plainly not the case.”  Meanwhile, the compound already had a trifluoromethyl group on it.  The petitioner could not explain why a chemist would add multiple additional fluorine atoms.

    ———————————————–

    Notes:

    On November 22, 2013, the U. S. Food and Drug Administration approved sorafenib (NEXAVAR tablets, Bayer Healthcare Pharmaceuticals Inc.) for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment. The FDA previously approved Sorafenib for treatment of renal cell carcinoma (2005) and hepatocellular carcinoma (2007).

    http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm376547.htm

    The U.S. Food and Drug Administration approved Stivarga® (regorafenib) on September 27, 2012 to treat patients with colorectal cancer that has progressed after treatment and spread to other parts of the body (metastatic). http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm321271.htm

    Petitioner Must Prove Injury to Have Standing to Appeal an IPR Decision

    January 11, 2017

    Phigenix v. ImmunoGen (Fed. Cir. 2017) (Wallach, J)

    • Even though § 141(c) allows a party to appeal a PTAB’s IPR decision, the statute does not necessarily establish Article III standing.
      • One of Article III’s requirements is proving Injury-in-Fact.
    • Even if a petitioner loses an IPR challenge (i.e., Patent is still valid), the Petitioner may still not have standing if the petitioner has not suffered any damages yet. (For Example, the patent owner hasn’t sued the petitioner yet for infringement.)
    • Here, Phigenix [petitioner] lost an IPR (i.e., Immunogen [patent owner] won with a ruling of non-obviousness). But Phigenix did not have standing to appeal the IPR loss to the Federal Circuit because Phigenix did not have standing in part because they have not suffered any injury/damages yet.
      • Phigenix did not argue that it risked infringing ImmunoGen’s patent.  Phigenix argued instead that it suffered “actual economic injury” because the mere existence of ImmunoGen’s patent increased competition between itself and ImmunoGen. The Federal Circuit did not find Phigenix’s argument persuasive.

    Claims:

    Claim 1:  An immunoconjugate comprising an anti-ErbB2 antibody conjugated to a maytansinoid, wherein the antibody is huMAb4D5-8.

    Claim 2:  The immunoconjugate of claim 1, wherein the maytansinoid is DM1 having the structure:
    US08337856-Image

    Related Blog Posts:

    Patently-O Blog Post on Phigenix v. ImmunoGen (Fed. Cir. 2017)

    PatentDocs Blog Post on Phigenix v. ImmunoGen (Fed. Cir. 2017)

    Bristol-Myers Squibb’s CTLA4Ig Formulation Patent Survives IPR Obviousness Challenge from Momenta Pharmaceuticals

    Momenta v. BMS

    January 3, 2016

    MOMENTA PHARMACEUTICALS, INC. (Petitioner)
    v.
    BRISTOL-MYERS SQUIBB COMPANY (Patent Owner)

    Case IPR2015-01537
    Patent 8,476,239
    FINAL WRITTEN DECISION
    December 22, 2016

    The PTAB concluded that the preponderance of the evidence did not support Momenta’s argument that the challenged claims would have been obvious.

    The claims of Patent US 8,476,239 are directed to stable liquid formulations of the therapeutic molecule CTLA4Ig.  CTLA4Ig is a protein molecule that is used to treat immune system diseases and disorders such as rheumatoid arthritis and adverse transplant reactions.

    Claim1:  A stable formulation suitable for subcutaneous administration comprising:
    [1]  at least 100mg/ml CTLA4Ig molecule,
    [2]  a sugar selected from the group consisting of sucrose, lactose, maltose, mannitol and trehalose and mixtures thereof and
    [3]  a pharmaceutically acceptable aqueous carrier, wherein the formulation has a
    [4]  pH range of from 6 to 8 and
    [5]  a viscosity of from 9 to 20 cps, and
    [6]  the weight ratio of sugar:protein is 1.1:1 or higher.
    (Bracketed numbers added)

    Momenta argued that the inventors did “nothing more than the efforts of a skilled formulator choosing from a limited set of known formulations to subcutaneous liquid formulations.” Momenta further argued that “the inventors went to the formulator’s toolbox and tried the first line of excipients and formulation parameters.  And they worked.” The PTAB agreed that the prior art references provided general guidance for formulating proteins as stable liquids and that BMS followed certain aspects of those general teachings when creating its stable liquid formulation comprising CLTA4Ig, a known protein.  Momenta’s cited evidence, however, did not persuade the PTAB that an ordinarily skilled artisan would have reasonably expected to be successful in achieving the claimed formulations. The evidence was not persuasive because, despite the prior art teaching of general guidance for formulating proteins as stable liquids, the prior art also taught that maintaining physical and chemical stabilities for most proteins in aqueous solution for an extended period is extremely difficult. Expert testimony about testimony about routine trial-and-error optimization did not overcome the statements of difficulty. Such statements of difficulty in the art indicated to the PTAB that there would not have been a reasonable expectation of success in achieving the claimed formulations.

    The PTAB highlighted in the importance of anticipated success and predictable results in determining obviousness. Citing the U.S. Supreme Court:

    When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.  If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.  In that instance the fact that a combination was obvious to try might show that it was obvious under § 103. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007) (emphasis added); compare Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 809 (Fed. Cir. 1989) (“Reached by means of routine procedures, and producing only predictable results, the recited dosages therefore do not distinguish the claims of the ’430 patent from the amiloride/hydrochlorothiazide combination that the district court properly found was disclosed in the ’813 patent.” (emphasis added)).

    Links:

    PDF of Final Decision (IPR2015-01537)

    Update 1/9/2017 – Link to Jones Day Blog:
    “Routine Trial-and-Error Approach to Protein Formulation Is Not Sufficient to Establish Obviousness Absent a Reasonable Expectation of Success in Achieving the Claimed Formulation”