UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`ARGENTUM PHARMACEUTICALS LLC
`
`Petitioner
`
`v.
`
`CIPLA LIMITED
`
`Patent Owner
`
`_____________________
`
`Case No. IPR2017-00807
`
`U.S. Patent No. 8,168,620
`_____________________
`
`PATENT OWNER PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107(a)
`
`
`
`
`
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`

`

`Patent Owner's Preliminary Response
` IPR2017-00807
`
`TABLE OF CONTENTS
`
`SUMMARY OF THE ARGUMENT ....................................................................... 1 
`
`I. 
`
`INTRODUCTION .......................................................................................... 6 
`
`A.
`
` 
`
`B.
`
` 
`
`C.
`
` 
`
`D.
`
` 
`
`The ’620 patent ...................................................................................... 6 
`
`Background of related litigation ............................................................ 7 
`
`Statement of relief requested ................................................................. 8 
`
`Person of ordinary skill in the art .......................................................... 8 
`
`II. 
`
`CLAIM CONSTRUCTION ........................................................................... 9 
`
`III.  THE BOARD SHOULD DENY TRIAL ON GROUNDS 1, 2, AND 3
`BECAUSE EACH HAS A THRESHOLD FAILURE. ............................... 12 
`
`A.
`
`  Anticipation Ground 1 presents the same anticipation
`argument using substantially the same art as was overcome
`during prosecution ............................................................................... 12 
`
`B.
`
` 
`
`Obviousness Grounds 2 and 3 are fatally deficient as a
`matter of law because Argentum failed to address various
`evidence of objective indicia of which it had knowledge. .................. 16 
`
`1. 
`
`2. 
`
`Argentum knew of Cipla’s well-developed objective
`indicia evidence because it observed, and its experts
`testified about, the same evidence in the Apotex trial. ............. 16 
`
`Cipla will be severely prejudiced if trial is instituted
`despite Argentum’s failure to address Cipla’s
`objective indicia evidence in its Petition. ................................ 19 
`
`IV.  THE BOARD SHOULD ALSO DENY TRIAL ON GROUNDS 1-3
`BECAUSE THEY LACK SUBSTANTIVE MERIT. ................................. 20 
`
`A.
`
`  Ground 1 Fails: Argentum has not established a reasonable
`likelihood that Claims 1 and 25 are anticipated by Segal. .................. 21 
`
`1. 
`
`Segal does not describe azelastine and fluticasone in
`single formulation. ................................................................... 21 
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`2. 
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`Patent Owner's Preliminary Response
` IPR2017-00807
`Segal does not enable the “nasal spray” / “dosage
`form suitable for nasal administration” of claims 1
`and 25. ...................................................................................... 24 
`
`B.
`
` 
`
`Ground 2 fails: Argentum has failed to establish a
`reasonable likelihood that Claims 1, 4-6, 24-26, and 29 are
`obvious over Segal, Hettche, and Phillipps. ........................................ 27 
`
`1. 
`
`The clinical art taught away from the co-
`administration of an antihistamine and a steroid. .................... 28 
`
`(a) 
`
`The art established that antihistamines and
`steroids had redundant mechanisms of action in
`vivo. ................................................................................ 29 
`(b)  Based on the results of the fixed co-
`administration studies, the prevailing clinical
`treatment Guidelines recommended using
`azelastine only as an “on demand” adjunct
`therapy. .......................................................................... 33 
`(c)  A POSA would have expected azelastine to
`decrease compliance with a fluticasone therapy. .......... 34 
`
`2. 
`
`3. 
`
`The art as a whole taught away from a fixed-dose
`combination of an antihistamine and a steroid. ....................... 37 
`
`In view of the anticipated formulation difficulties, a
`POSA would not have been motivated to formulate
`azelastine and fluticasone into a nasal spray with a
`reasonable expectation of success. ........................................... 38 
`
`(a)  Argentum fails to establish that co-formulating
`azelastine and fluticasone into a combination
`formulation was known in 2002. ................................... 39 
`(b)  No reasonable expectation of success exists
`because a POSA knew that combining
`fluticasone with another active ingredient in a
`suspension formulation led to aggregation. ................... 40 
`(c)  No reasonable expectation of success exists
`because Cramer’s Example III—the USPTO’s
`asserted closest prior art—is not suitable for
`nasal administration. ...................................................... 41 
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`Patent Owner's Preliminary Response
` IPR2017-00807
`
`C.
`
` 
`
`Ground 3 Fails: Argentum has failed to establish a
`reasonable likelihood that claims 42-44 would have been
`obvious over Segal, Hettche, Phillipps, and Flonase® Label. ............. 42 
`
`1. 
`
`2. 
`
`The Petition does not articulate a motivation to
`combine Hettche, Phillipps, Segal, and Flonase®
`Label. ........................................................................................ 42 
`
`The Board should deny trial on Ground 3 because the
`art taught away from the excipients recited in claims
`42-44. ....................................................................................... 44 
`
`(a) 
`
`(b) 
`
`(c) 
`
`The art taught away from using
`microcrystalline cellulose and sodium
`carboxymethyl cellulose with cationic drugs
`like azelastine salts. ....................................................... 44 
`The art taught away from using three
`preservatives: benzalkonium chloride, edetate
`disodium, and phenyl ethyl alcohol. .............................. 46 
`The art taught away from using glycerin as a
`isotonic agent. ................................................................ 47 
`
`D.
`
`  Grounds 2 and 3 Fail: Compelling objective indicia of non-
`obviousness support the validity of the challenged claims. ................ 48 
`
`1. 
`
`2. 
`
`Cipla’s objective indicia evidence has a nexus to the
`challenged claims. .................................................................... 48 
`
`Unexpected results: The claimed formulation exhibits
`unexpected formulation and clinical results. ........................... 49 
`(a)  Dymista® unexpectedly surpasses the efficacy
`of both commercial and reformulated
`fluticasone. ..................................................................... 49 
`(i) 
`The closest prior art from a clinical
`perspective is the fixed dosing studies,
`which are the only evidence of an
`antihistamine and steroid being dosed
`consistently prior to the date of
`invention. .............................................................. 49 
`(ii)  Dymista® is unexpectedly more effective,
`faster-acting, and safer than the prior art. ............ 50 
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`(b) 
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`Patent Owner's Preliminary Response
` IPR2017-00807
`The claimed formulations are unexpectedly
`suitable for nasal administration in light of the
`prior art. ......................................................................... 53 
`
`Failure of Others: sophisticated pharmaceutical
`companies failed to develop a combined formulation. ............ 53 
`
`Acquiescence: Meda’s decision to take a royalty-
`bearing license to Cipla’s patents supports
`nonobviousness. ....................................................................... 55 
`
`Skepticism: Both Meda and FDA were skeptical of
`the feasibility and desirability of a fixed-dose
`azelastine/fluticasone formulation. .......................................... 56 
`Commercial Success: Sales of Dymista® in the U.S.
`and Duonase in India demonstrate nonobviousness. ............... 57 
`Unmet Need: Dymista® satisfied a long-felt but unmet
`need for better AR treatment. ................................................... 59 
`
`No alleged “blocking patents” undercut Cipla’s
`commercial success and long-felt need evidence. ................... 61 
`
`3. 
`
`4. 
`
`5. 
`
`6. 
`
`7. 
`
`8. 
`
`9. 
`
`Copying: Duonase was subjected to widespread
`copying in India. ...................................................................... 63 
`Praise: Industry leaders praised Dymista®. .............................. 63 
`CONCLUSION ............................................................................................. 64 
`
`10. 
`
`- iv -
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`V. 
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`

`

` IPR2017-00807
`Patent No. 8,168,620
`
`SUMMARY OF THE ARGUMENT
`
`Patent Owner Cipla Ltd. (“Cipla”) provides this preliminary response to
`
`Petitioner Argentum Pharmaceuticals LLC’s (“Argentum”) Petition for inter partes
`
`review of claims 1, 4-6, 24-26, 29, and 42-44 of U.S. Patent No. 8,168,620 (“the
`
`’620 patent”; EX1001) in accordance with 37 C.F.R. § 42.107(a). The Board
`
`should deny institution on all three grounds identified in Argentum’s Petition—
`
`anticipation Ground 1 and obviousness Grounds 2 and 3—for failure to address
`
`threshold legal issues, or because its arguments fail on the merits, or both.
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`The Board should deny instituting trial for the following two threshold
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`failures:
`
`First, Ground 1 of Argentum’s Petition presents “the same or substantially
`
`the same prior art or arguments [that] previously were presented to the Office.” 35
`
`U.S.C. § 325(d). Argentum relies on WO 98/48839 (“Segal”) to argue that a fixed-
`
`dose combination of azelastine and fluticasone was previously disclosed in the
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`prior art. But Segal was already before the U.S. Patent and Trademark Office
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`(“USPTO”) during prosecution, as was the more specific teachings of EP No.
`
`0780127 (“Cramer”), and Cipla overcame both by showing that Cramer did not
`
`teach a dosage form “suitable for nasal administration” or a “nasal spray,” as
`
`recited by the claims. Because Argentum has not shown that Segal discloses or
`
`enables a “nasal spray” or dosage form that is “suitable for nasal administration,”
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`Patent Owner's Preliminary Response
` IPR2017-00807
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`the Board should deny institution of Ground 1.
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`Second, Grounds 2 and 3 are also defective as a matter of law because
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`Argentum failed to address significant publicly-available evidence of objective
`
`indicia of non-obviousness of which Argentum was indisputably aware. In
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`December 2016, the ’620 patent was tried in the District of Delaware. An in-house
`
`legal representative of Argentum attended that trial and saw Cipla’s evidence of
`
`eight objective indicia of non-obviousness. The evidence was also the subject of
`
`extensive pre- and post-trial submissions readily available to Argentum and the
`
`public.
`
`Additionally, both of Argentum’s declarants here—Drs. Schleimer and
`
`Donovan—provided expert testimony concerning objective indicia of non-
`
`obviousness on behalf of Apotex at trial. CIP2018, 27-28. The Board would be left
`
`uninformed of that fact based on Argentum’s Petition (despite being filed just over
`
`a month after trial ended). Instead of challenging the well-developed trial evidence
`
`it witnessed, Argentum’s Petition responds only to the objective indicia evidence
`
`submitted during patent prosecution. That is not enough. Even Dr. Robert
`
`Schleimer, Argentum’s expert, acknowledges in his declaration that “one must also
`
`consider whether there are any secondary considerations that support the non-
`
`obviousness of the invention,” listing many of the indicia presented at trial.
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`EX1003, ¶43. Yet, neither he nor Argentum addressed these considerations it its
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`Patent Owner's Preliminary Response
` IPR2017-00807
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`Petition.
`
`The law requires Argentum, as the patent challenger, to address all available
`
`objective indicia of non-obviousness in its Petition. See Leo Pharm. Prods., Ltd. v.
`
`Rea, 726 F.3d 1346, 1357 (Fed. Cir. 2013) (“Whether before the Board or a court,
`
`this court has emphasized that consideration of the objective indicia is part of the
`
`whole obviousness analysis, not just an afterthought.”) (citations omitted, emphasis
`
`in original). Because Argentum knew of this evidence and deliberately chose to
`
`ignore it to Cipla’s prejudice, the Board should deny institution on obviousness
`
`Grounds 2 and 3.
`
`Argentum’s Petition also fails on the merits because all three asserted
`
`grounds suffer fatal substantive shortcomings. Ground 1, asserting that claims 1
`
`and 25 of the ’620 patent are anticipated in view of Segal, is flawed because a
`
`person of ordinary skill in the art (“POSA”) would not have immediately
`
`envisaged the claimed combination of azelastine hydrochloride (“azelastine”) and
`
`fluticasone propionate (“fluticasone”) from the more than 800 million possible
`
`combinations Segal discloses. Moreover, Segal provides no disclosure or teaching
`
`that would have enabled a POSA to arrive at a pharmaceutical formulation
`
`combining azelastine and fluticasone that is “suitable for nasal administration”
`
`or in a combined “nasal spray,” which are required limitations of claims 1 and 25.
`
`Ground 1 is also duplicative of the rejection made and overcome by the
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`Patent Owner's Preliminary Response
` IPR2017-00807
`patentee during prosecution. Indeed, the sole teaching for which Argentum relies
`
`on Segal—the disclosure of azelastine and fluticasone among millions of other
`
`disclosed combinations—was also alleged by the Examiner to have been disclosed
`
`in the Cramer reference. Cipla overcame Cramer’s more specific disclosure by
`
`demonstrating that it did not teach a combined “nasal spray” formulation that was
`
`“suitable for nasal administration.” Accordingly, Segal does not provide an
`
`anticipatory disclosure.
`
`Argentum’s Ground 2 asserting obviousness of claims 1, 4-6, 24-26, and 29
`
`in view of U.S. Patent No. 4,335,121 (“Phillipps”), U.S. Patent No. 5,164,194
`
`(“Hettche”), and Segal is equally deficient. The cited references would not have
`
`motivated or otherwise provided a POSA any reason to combine azelastine and
`
`fluticasone into the claimed fixed-dose combination formulation. Rather, at the
`
`time of the invention, the art taught that: (1) co-administering an antihistamine,
`
`like azelastine, with an intranasal corticosteroid, like fluticasone, resulted in no
`
`meaningful clinical improvement over a steroid alone; (2) co-administering an
`
`antihistamine and a steroid was expected to increase side effects experienced by
`
`patients, and thus decrease compliance; and (3) a fixed-dose combination
`
`decreased the flexibility mandated by the prevailing allergic rhinitis treatment
`
`guidelines Argentum cites and the well-established approaches practiced in the art.
`
`Argentum’s Petition provides no support for a POSA deviating from what the art
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`Patent Owner's Preliminary Response
` IPR2017-00807
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`taught.
`
`Indeed, as Argentum’s expert Dr. Robert Schleimer admitted at trial, before
`
`Cipla’s invention, no one, anywhere in the world, had successfully developed a
`
`nasal spray with two active ingredients, much less a steroid and an antihistamine in
`
`a single nasal spray formulation. CIP2019, 43:5-44:2. And Dymista®—the U.S.
`
`commercial embodiment—was the first, and still is the only, FDA-approved, fixed-
`
`dose combination nasal spray formulation. These facts alone demonstrate the non-
`
`obviousness of Cipla’s invention. Leo, 726 F.3d at 1358.
`
`Moreover, even if a POSA had a reason to combine azelastine and
`
`fluticasone into a fixed-dose combination, known formulation difficulties would
`
`have dissuaded a POSA from trying it. And, even if it were tried, a POSA would
`
`not have had any reasonable expectation of success of formulating the claimed
`
`combination. For example, fluticasone was known to aggregate and precipitate
`
`from its suspended state when co-formulated with other active ingredients. A
`
`POSA following what the USPTO determined to be the closest prior art—Cramer’s
`
`Example III—would have arrived at a pharmaceutical formulation that was not
`
`suitable for nasal administration. A POSA would not have been able to fix all of
`
`the shortcomings with any reasonable expectation of success. And, notably,
`
`Segal’s disclosure is substantially less detailed than Cramer’s Example III.
`
`Finally, Argentum’s Ground 3 asserting obviousness of claims 42-44 in
`
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`Patent Owner's Preliminary Response
` IPR2017-00807
`view of Hettche, Phillipps, Segal, and the Flonase® label is flawed because the
`
`Petition provides no evidence that a POSA would have been motivated to combine
`
`the cited prior art references to arrive at the claimed invention. While Ground 3
`
`suffers from all the same flaws as Ground 2, Ground 3 goes even further astray in
`
`its hindsight selection of claimed excipients, including use of excipients explicitly
`
`discouraged by the relevant art.
`
`There are also eight significant objective indicia of non-obviousness that
`
`further defeat Grounds 2 and 3. Given that these considerations “must always when
`
`present be considered,” Argentum’s obviousness analysis is incomplete as a matter
`
`of law. Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 752 F.3d 967, 977
`
`(Fed. Cir. 2014). Thus, the Board should deny institution of Argentum’s Petition
`
`because Argentum failed to meet its legal burden.
`
`I.
`
`INTRODUCTION
` The ’620 patent
`The ’620 patent is directed to compositions containing azelastine and
`
`A.
`
`fluticasone, along with specific pharmaceutical excipients. CIP2007, ¶21. The
`
`application that matured into the ’620 patent was filed on June 13, 2003 as
`
`PCT/GB03/02557 and claims priority to GB 0213739.6, filed June 14, 2002, under
`
`35 U.S.C. § 119.1 Duonase, a commercial embodiment in India, was not only the
`
`
`1 Argentum claims to have “preserve[d]” some right to challenge the priority
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`Patent Owner's Preliminary Response
` IPR2017-00807
`first-ever fixed-dose nasal spray combination of an antihistamine and a steroid, but
`
`it was also the first fixed-dose nasal spray combination of any type, anywhere in
`
`the world. Dymista®, a commercial embodiment in the U.S., was the first, and
`
`today remains the only, FDA-approved fixed-dose nasal spray combination
`
`formulation.
`
`B.
`
`Background of related litigation
`
`
`The ’620 patent is listed in the Food and Drug Administration’s (“FDA”)
`
`Orange Book in connection with the drug Dymista®, which is approved for the
`
`treatment of seasonal allergic rhinitis (“AR”). Apotex Inc. and Apotex Corp.
`
`(“Apotex”) filed an Abbreviated New Drug Application (“ANDA”) seeking
`
`approval to introduce a generic copy of Dymista®. In response, Cipla (along with
`
`its exclusive licensee, Meda Pharmaceuticals) sued Apotex in the District of
`
`Delaware in December 2014 asserting infringement of the ’620 patent. Meda
`
`Pharm., Inc. v. Apotex, Inc., Civ. No. 14-1453 (D. Del.). The Court held a bench
`
`trial from December 13-16, 2016, and closing arguments occurred in March 2017.2
`
`All trial and hearing transcripts, and all post-trial submissions were publicly
`
`
`date, but has failed to articulate any basis for any challenge “with particularity” as
`
`required under 35 U.S.C. § 312(a)(3). Accordingly, the Board should reject
`
`Argentum’s unsupported priority challenge and deem it waived.
`
`2 The parties settled the district court dispute in May 2017.
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`Patent Owner's Preliminary Response
` IPR2017-00807
`available to Argentum from the Court’s docket. And, moreover, Argentum’s
`
`declarants in this IPR—Drs. Robert Schleimer and Maureen Donovan—served as
`
`testifying experts on behalf of Apotex at trial on the same issue of the ’620 patent’s
`
`validity. Finally, Argentum admitted that “[it] attended the public portions of the
`
`trial.” CIP2127, 1. Because no part of trial was ever closed to the public, Argentum
`
`attended the entire trial.
`
`C.
`
`Statement of relief requested
`
`
`Cipla submits that the Board should deny institution of Argentum’s Petition
`
`for the reasons explained in this preliminary response.
`
`D.
`
`Person of ordinary skill in the art
`
`
`The hypothetical POSA in the field of the ’620 patent would have education
`
`and experience in both (1) the treatment of patients suffering from AR and (2) the
`
`development of drug formulations. From the clinical perspective, a POSA would
`
`have the experience of a primary care physician with a medical degree and 2-4
`
`years of experience. CIP2001, ¶19. From the formulation perspective, a POSA
`
`would possess a bachelor of science degree in pharmaceutical sciences and 4-5
`
`years of experience as a formulator, although the POSA could also be a person
`
`with a higher level of formal education and fewer years of experience. CIP2007,
`
`¶¶19-20.
`
`Argentum’s proposed definition differs in that it incorrectly renders optional
`
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`Patent Owner's Preliminary Response
` IPR2017-00807
`clinical experience in treating patients. Pet. 11. By omitting the critical clinical
`
`experience of a POSA, Argentum’s arguments seek to rely only on laboratory
`
`models. Argentum’s limited view is problematic because it overlooks the
`
`significant body of clinical literature at the time of invention, discussed below,
`
`showing that antihistamines and steroids had redundant activity in vivo.
`
`II. CLAIM CONSTRUCTION
`“Conditions”
`
`The parties agree that “conditions” means “disease(s) or illness(es),” as
`
`construed in the related Apotex litigation.
`
`“Nasal Spray” / “Suitable for Nasal Administration”
`
`Argentum’s Petition fails to proffer constructions for the terms “nasal
`
`spray” and “suitable for nasal administration.” Those terms each should be
`
`construed to require “pharmaceutical formulations that are tolerable to
`
`patients, that are homogeneous, and that can be suitably deposited onto the
`
`nasal mucosa,” consistent with Cipla’s arguments during prosecution. CIP2001,
`
`¶26; CIP2007, ¶23.
`
`The Board applies the “broadest reasonable construction” to the terms and
`
`phrases of unexpired patents. Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131,
`
`2142 (2016); 37 C.F.R. § 42.100(b). That said, “their broadest reasonable
`
`interpretation … does not include giving claims a legally incorrect interpretation.”
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`In re Skvorecz, 580 F.3d 1262, 1267 (Fed. Cir. 2009); D’Agostino v. Mastercard
`
`Int’l Inc., 844 F.3d 945, 948 (Fed. Cir. 2016). Here, the Board “should [] consult
`
`the patent’s prosecution history in proceedings in which the patent has been
`
`brought back to the agency for a second review” to see if a construction would be
`
`“legally incorrect.” Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed.
`
`Cir. 2015); D’Agostino, 844 F.3d at 948.
`
`During prosecution, the Examiner initially rejected Cipla’s application under
`
`35 U.S.C. §§ 102 and 103 over the Cramer reference, and specifically the
`
`formulation disclosed in Example III. CIP2001, ¶27; CIP2007, ¶¶23-24; EX1002,
`
`507-522. In response, Cipla submitted a declaration from co-inventor Geena
`
`Malhotra recreating Cramer’s Example III. The declaration and recreation
`
`demonstrated that Cramer’s Example III formulation exhibited: (1) unacceptable
`
`osmolality, which would have caused irritation to patients; (2) unacceptable spray
`
`quality, which would not have suitably deposited onto the nasal mucosa; and (3)
`
`unacceptable settling, which would have adversely effected homogeneity of the
`
`formulation. EX1002, 286-287, 220-221. Together, these problems rendered
`
`Example III unsuitable for use as a nasal spray. Id.; CIP2001, ¶28; CIP2007, ¶25.
`
`In view of this testing, and to overcome the prior art rejection, Cipla also
`
`amended the claims to recite “said pharmaceutical formulation is in a dosage form
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`Patent Owner's Preliminary Response
` IPR2017-00807
`suitable for nasal administration,” and likewise noted that certain pending claims
`
`recited a “nasal spray.” EX1002, 203-231; CIP2001, ¶¶29-30; CIP2007, ¶25.
`
`Cipla argued that the Malhotra declaration established that “Example 3 of
`
`Cramer (identified by the April 28, 2010 Office Action, page 16, as the closest
`
`example) is inoperable and unacceptable as a pharmaceutical formulation in a
`
`dosage
`
`form suitable
`
`for nasal administration” because
`
`it exhibited an
`
`unacceptable osmolality, unacceptable spray quality, and unacceptable settling and
`
`that “the inoperability of Cramer’s closest example as cited by the Office Action is
`
`a further basis for the novelty of independent claims 1 [and] 56….” EX1002, 220-
`
`21 (emphasis added).
`
`Based on the declaration, arguments, and amendments, the Examiner later
`
`allowed the pending claims over Cramer. EX1002, 38-40. A POSA would have
`
`understood from Cipla’s claim amendments, declaration, and arguments that the
`
`formulations recited in the challenged claims do not suffer from unacceptable
`
`osmolality, unacceptable spray quality, and unacceptable settling, as distinguished
`
`from Cramer’s Example III which was proven inoperable. CIP2001, ¶31; CIP2007,
`
`¶¶25, 44-47.
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`Patent Owner's Preliminary Response
` IPR2017-00807
`III. THE BOARD SHOULD DENY TRIAL ON GROUNDS 1, 2, AND 3
`BECAUSE EACH HAS A THRESHOLD FAILURE.
` Anticipation Ground 1 presents the same anticipation argument
`using substantially the same art as was overcome during
`prosecution
`
`A.
`
`The Board should deny trial on Argentum’s anticipation Ground 1 as
`
`redundant under 35 U.S.C. § 325(d) because it presents the same arguments on
`
`substantially the same prior art that was already overcome during prosecution.
`
`Because Cipla already overcame these same arguments in view of substantially the
`
`same prior art during prosecution, the Board should deny institution here.
`
`As discussed above (§II), Cipla overcame Cramer’s alleged anticipatory
`
`disclosure by inter alia, (1) demonstrating that Cramer’s Example III formulation
`
`was not a nasal spray suitable for nasal administration, and (2) amending the
`
`claims. Aware of Cramer’s shortcomings, Argentum relies on Segal, a reference its
`
`expert, Dr. Schleimer, testified is “less specific” than Cramer, to assert the same
`
`anticipation argument. CIP2019, 65:17-20.
`
`As shown in the chart below, each teaching in Segal to which Argentum
`
`points in its Petition was also before the Examiner during prosecution by way of
`
`Cramer:
`
`’620 Patent Claims Segal (Pet. 19-21)
`
`Cramer (EX1011)
`
`1. A pharmaceutical
`formulation
`comprising:
`
`“The present invention
`provides topically applicable
`nasal compositions
`
`“The present invention
`relates to novel nasal spray
`compositions,” EX1011,
`
`
`
`- 12 -
`
`

`

`comprising a therapeutically
`effective amount of a topical
`antiinflammatory agent and a
`therapeutically effective
`amount of at least one agent
`suitable for topical nasal
`administration and selected
`from the group consisting of a
`vasoconstrictor, a
`neuramidinase inhibitor, an
`anticholinergic agent, a
`leukotriene inhibitor, an
`antihistamine, an antiallergic
`agent, an anesthetic, and a
`mucolytic agent.” EX1012,
`4:10-15; see also id. cl.1.
`“Suitable antihistamines are
`diphenhydramine,
`chlorpheniramine, cetirizine
`terfenadine, fenofexadine,
`astemizole norastemizole,
`azelastine, and azatidine.”
`EX1012, 5:19-20; see also id.
`cl.4 (depending from Segal
`claim 1).
`
`“In a preferred embodiment
`the topical antiinflammatory
`agent is beclomethasone
`diproprionate, budesonide,
`dexamethasone, mometasone
`furoate, fluticasone
`propionate or triamcinolone
`acetonide.” EX1012, 4:23-26;
`see also id. cl.2 (depending
`from Segal claim 1).
`
`Patent Owner's Preliminary Response
` IPR2017-00807
`2:5; EX1002, 511.
`
`The present invention
`comprises an
`“antihistamine selected
`from the group consisting
`of cetirizine, loratadine,
`azelastine,
`pharmaceutically
`acceptable salts thereof,
`optically active racemates
`thereof and mixtures
`thereof.” EX1011, 2:36-43;
`EX1002, 511.
`The present invention
`comprises a
`“glucocorticoid selected
`from the group consisting
`of beclomethasone,
`flunisolide, triamcinolone,
`fluticasone, mometasone,
`budesonide,
`pharmaceutically
`acceptable salts thereof and
`mixtures thereof.” EX1011,
`2:36-40; EX1002, 511.
`
`(a) azelastine, or a
`pharmaceutically
`acceptable salt
`thereof, and
`
`(b) a
`pharmaceutically
`acceptable ester of
`fluticasone,
`
`
`
`- 13 -
`
`

`

`Patent Owner's Preliminary Response
` IPR2017-00807
`
`(c) wherein said
`pharmaceutical
`formulation is in a
`dosage form suitable
`for nasal
`administration.
`
`“The compositions of the
`present invention are
`formulated as aqueous
`solutions comprising an
`antiinflammatory agent and at
`least one additional
`therapeutic agent and further
`comprising a
`pharmaceutically acceptable
`nasal carrier…Preferred nasal
`formulations are nose drops
`or nasal sprays containing a
`water buffered aqueous
`solution as a carrier.”
`EX1012, 5:29-4:5; see also
`id. cl.15 (depending from
`Segal claim 1 or 11).
`
`Segal provided no examplary
`formulations.
`
`25. A nasal spray
`formulation
`comprising
`
`“The compositions of the
`present invention are
`formulated as aqueous
`solutions comprising an
`antiinflammatory agent and at
`
`
`
`- 14 -
`
`
`
`EX1011, 6:30-41. This
`purported nasal spray
`example from Cramer
`discloses an aqueous
`carrier, the same
`formulation information
`Argentum identified in
`Segal. See also EX1011,
`3:34-35 (describing
`aqueous saline solution
`carriers).
`
`The above exemplary
`formulation from Cramer,
`Example III, is the closest
`prior art as confirmed by
`the PTO (EX1002, 519-
`520), and was shown
`during prosecution and
`again during litigation to be
`unsuitable for nasal
`administration due to its
`unacceptable acidity,
`instability, and inconsistent
`dosage delivery. EX1002,
`284-287; see also CIP2029;
`CIP2030.
`See supra claim limitation
`1(c).
`
`

`

`Patent Owner's Preliminary Response
` IPR2017-00807
`
`least one additional
`therapeutic agent and further
`comprising a
`pharmaceutically acceptable
`nasal carrier…Preferred nasal
`formulations are nose drops
`or nasal sprays containing a
`water buffered aqueous
`solution as a carrier.”
`EX1012, 5:29-6:5; see also
`id. cl.15 (depending from
`Segal claim 1 or 11).
`“Suitable antihistamines are
`diphenhydramine,
`chlorpheniramine, cetirizine
`terfenadine, fenofexadine,
`astemizole norastemizole,
`azelastine, and azatidine.”
`EX1012, 5:19-20; see also id.
`cl.4 (depending from Segal
`claim 1).
`“In a preferred embodiment
`the topical antiinflammatory
`agent is beclomethasone
`diproprionate, budesonide,
`dexamethasone, mometasone
`furoate, fluticasone
`propionate or triamcinolone
`acetonide.” EX1012, 4:23-26;
`see also id. cl.2 (depending
`from Segal claim 1).
`“Preferred nasal formulations
`are nose drops or nasal sprays
`containing a water buffered
`aqueous solution as a carrier.”
`EX1012, 6:4-5.
`
`(i) azelastine, or a
`pharmaceutically
`acceptable salt
`thereof,
`
`(ii) a
`pharmaceutically
`acceptable ester of
`fluticasone,
`
`and (iii) a
`pharmaceutically
`acceptable carrier or
`excipient therefor.
`
`
`
`- 15 -
`
`See supra claim limitation
`1(a).
`
`See supra claim limitation
`1(b).
`
`“One other essential
`component of the present
`invention is a
`pharmaceutically-
`acceptable intranasal
`carrier. Preferred for use
`herein are aqueous saline
`solution carriers.” EX1011,
`3:34-35.
`
`

`

`Patent Owner's Preliminary Response
` IPR2017-00807
`Moreover, Argentum’s Petition makes no mention of the above claim
`
`amendments or Cipla’s arguments, nor their importance in overcoming Cramer
`
`during prosecution. Nor has Argentum proffered any evidence to suggest that
`
`Segal discloses a dosage form that is “suitable for nasal administration” or a “nasal
`
`spray” as required by the challenged claims.
`
`The Board should deny Ground 1 because it presents “the same or
`
`substantially the same prior art [and] arguments” that Cipla already overcame
`
`during prosecution. See, e.g., Yotrio Corp. v. Lakesouth Holdings, LLC, IPR2017-
`
`00298, Paper 12, 7-14 (PTAB May 15, 2017); IPR2017-00299, Paper 7, 9-14
`
`(PTAB May 15, 2017).
`
`B.
`
` Obviousness Grounds 2 and 3 are fatally deficient as a matter of
`law because Argentum failed to address various evidence of
`objective indicia of which it had knowledge.
`1.
`
`Argentum knew of Cipla’s well-developed objective indicia
`evidence because it observed, and its experts testified about,
`the same eviden