Paper No. 36
`Filed: November 15, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner.
`____________
`
`Case PGR2018-00001
`U.S. Patent No. 9,539,268
`____________
`
`PETITIONER’S REPLY
`
`
`Filed: November 15, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`GRÜNENTHAL GMBH,
`
`Petitioner
`
`v.
`
`ANTECIP BIOVENTURES II LLC,
`
`Patent Owner.
`____________
`
`Case PGR2018-00001
`U.S. Patent No. 9,539,268
`____________
`
`PETITIONER’S REPLY
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`LEONARD ANTICIPATES CLAIM 23 ........................................................4
`
`CLAIM 23 IS OBVIOUS OVER LEONARD ALONE .................................6
`
`III. CLAIMS 23-30 ARE OBVIOUS OVER LEONARD,
`ARONHIME AND THE MERRION POSTER..............................................8
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Claim 23 Is Anticipated by Aronhime and Is Therefore
`Obvious..................................................................................................8
`
`Claim 23 Is Obvious Over Leonard and Aronhime ............................11
`
`The Merrion Poster Is Prior Art ..........................................................14
`
`Ground 8 Does Not Fail if the Merrion Poster Is Not
`Prior Art...............................................................................................15
`
`Claims 24-30 Are Obvious Over Leonard, Aronhime and
`the Merrion Poster...............................................................................16
`
`IV. CLAIMS 3-15 ARE OBVIOUS OVER LEONARD, THE
`MERRION POSTER, FOX AND LASLETT...............................................17
`
`V.
`
`VI.
`
`NO SECONDARY CONSIDERATIONS SUPPORT
`PATENTABILITY........................................................................................17
`
`IF NOT OBVIOUS, CLAIMS 3-30 ARE INVALID FOR
`LACK OF ENABLEMENT ..........................................................................18
`
`VII. CLAIMS 15-22 ARE INVALID FOR LACK OF
`ENABLEMENT ............................................................................................22
`
`VIII. CONCLUSION..............................................................................................24
`
`i
`
`
`
`TABLE OF AUTHORITIES
`
`Cases
`Atlas Powder Co. v. IRECO Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) .....................................................................10
`
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) .......................................................................5
`
`Connell v. Sears Roebuck & Co.,
`722 F.2d 1542 (Fed. Cir. 1983) .....................................................................11
`
`Genentech Inc. v. Novo Nordisk, A/S,
`108 F.3d 1361 (Fed. Cir. 1997) .....................................................................18
`
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) .......................................................................8
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .....................................................................10
`
`In re McDaniel,
`293 F.3d 1379 (Fed. Cir. 2002) .....................................................................11
`
`In re Wertheim,
`541 F.2d 257 (C.C.P.A. 1976).........................................................................6
`
`Ineos USA LLC v. Berry Plastics Corp.,
`783 F.3d 865 (Fed. Cir. 2015) .........................................................................5
`
`Merck & Co. v. Biocraft Labs., Inc.,
`874 F.2d 804 (Fed. Cir. 1989) .........................................................................8
`
`Peters v. Active Mfg. Co.,
`129 U.S. 530 (1889).........................................................................................5
`
`Polaroid Corp. v. Eastman Kodak Co.,
`789 F.2d 1556 (Fed. Cir. 1986) .......................................................................5
`
`ii
`
`
`
`In a continuing struggle to point to something—anything—inventive in the
`
`’268 and related patents, Patent Owner has once again recast its assertions of
`
`novelty and nonobviousness as follows: The ’268 specification “teaches a person
`
`of ordinary skill in the art (“POSA”) (1) that a dosage form of zoledronic acid with
`
`a bioavailability range of about 1.1% to about 4% is effective to treat disease, and
`
`(2) that one can formulate a dosage form within the recited bioavailability range
`
`simply by selecting certain forms of zoledronic acid, e.g. salt forms, which have
`
`unexpectedly higher bioavailability, without the need to use enhancers . . . .” Paper
`
`22 (“POR”) at 1. The ’268 patent teaches nothing of the sort.
`
`As to (1), the ’268 inventor made no discoveries regarding efficacy of
`
`zoledronic acid dosage forms having bioavailabilities in the claimed ranges. For
`
`one, there is no such thing as a particular bioavailability at which a dosage form
`
`becomes effective in treating disease. Whether a drug has efficacy depends on the
`
`total amount of drug that reaches its site of action, which in turn depends on
`
`potency. As an example, Patent Owner’s expert, Dr. Wargin, testified that 100 mg
`
`of a zoledronic acid dosage form with a bioavailability of 1% or a 200 mg dose
`
`with a bioavailability of 0.5% will produce the same therapeutic effect as the 50
`
`mg dose of AXS-02 with a bioavailability of 2% reported in Exh. 2026. Exh. 1093
`
`45:4-46:11. Thus, in Dr. Wargin’s words, there is nothing “magical” about the
`
`claimed bioavailability ranges. Id. 61:14-21.
`
`1
`
`
`
`Indeed, Dr. Wargin admitted that not only did his counsel write ¶19 of his
`
`declaration (the basis for the quotation in the opening paragraph above), he found
`
`the use of the word “effective” as it relates to bioavailability “troublesome” and
`
`proposed rewriting that sentence to include information about specific doses. Id.
`
`48:16-49:11; see also 46:12-22 (Dr. Wargin: “I don’t usually think of
`
`bioavailability in terms of effectiveness”). Moreover, Patent Owner’s assertion is
`
`premised upon the notion that the prior art taught that zoledronate dosage forms
`
`with a bioavailability of about 1.1% to about 4% were considered ineffective. This
`
`is certainly not the case, as noted by Dr. Wargin who testified that as of May 2014
`
`a POSA would have had “every reason to believe that a dose adjustment of a 3
`
`percent bioavailability would provide concentrations that were efficacious.” Id.
`
`112:15-23; see also 109:4-13 (Dr. Wargin testifying that the prevailing view as of
`
`May 2014 as to zoledronic acid dosage forms having bioavailabilities less than 5%
`
`“would be that they certainly would be effective”). In other words, as Dr. Wargin
`
`admitted, there is no additional information in the ’268 patent as to the efficacy of
`
`zoledronic acid forms over what was already known in the prior art. Id. 125:25-
`
`126:6. In fact, there is no efficacy data whatsoever in the ’268 patent. Id.
`
`2
`
`
`
`With respect to Patent Owner’s assertion (2), the ’268 inventor was not the
`
`first to create an oral dosage form having the claimed bioavailabilities, as admitted
`
`by Dr. Wargin:
`
`Q. . . . But a POSA would not have understood the
`inventor of the ’268 patent to be the first to develop an
`oral formulation of zoledronic acid with a bioavailability
`between 1.1 and 4 percent?
`
`A. True. But those formulations would have used
`enhancers or other mechanisms.
`
`Q. And that was taught by Leonard?
`
`A. That was taught by Leonard.
`
`Id. 93:19-94:1. And, with respect to an unenhanced form, that was invented by
`
`Aronhime. Id. 40:6-18.
`
`Yet, even if the inventor had been the first to discover a zoledronic acid
`
`dosage form having a bioavailability within the claimed ranges without the
`
`addition of an enhancer, or the effectiveness of such dosage forms, neither
`
`discovery would be legally relevant. Claims 3-22 cover oral administration of
`
`zoledronic acid dosage forms having a particular bioavailability to patients with
`
`knee pain, while claims 23-30 cover zoledronate salt forms having a particular
`
`bioavailability. Both sets of claims are devoid of any limitations regarding either
`
`(1) efficacy against any particular condition or (2) the presence or absence of
`
`enhancers. Thus, neither achieving efficacy nor obtaining particular
`
`3
`
`
`
`bioavailabilities in the absence of enhancers are features of the alleged invention,
`
`let alone a distinguishing feature over the prior art. Therefore, even accepting as
`
`true Patent Owner’s alleged discoveries, claims 3-30 still lack novelty and/or are
`
`obvious over the prior art.
`
`I.
`
`LEONARD ANTICIPATES CLAIM 23
`
`Leonard discloses all of the limitations of claim 23. Leonard claim 2 covers
`
`oral dosage forms of zoledronic acid and a medium chain fatty acid excipient
`
`wherein the dosage form has a bioavailability of 2.5% to 13.0%. Exh. 1005 ¶114;
`
`Exh. 1009 col. 35, ll. 12-21. Although the human study that gave rise to the
`
`invention of claim 2 used the free acid, claim 2 is not so limited. Leonard states
`
`that “[i]n embodiments in which the drug comprises a bisphosphonate, the drug
`
`may be selected from the group that includes the free acid forms and biologically
`
`acceptable salts of . . . zoledronate and derivatives thereof.”1 Id. col. 4, ll. 8-13
`
`(emphasis added). Any dosage form containing zoledronic acid, including salt
`
`forms, and a medium chain fatty acid enhancer having a bioavailability of between
`
`1 Leonard also provides data showing sodium caprate enhances the bioavailability
`
`of another bisphosphonate salt. Exh. 1093 115:2-116:15.
`
`4
`
`
`
`2.5% and 13% falls within the scope of Leonard claim 2.2 Thus, Leonard plainly
`
`discloses “[a] pharmaceutical dosage form . . . comprising . . . zoledronic acid in a
`
`salt form” as required by claim 23.
`
`Put another way, any such dosage form having a bioavailability at the lower
`
`end of the range of Leonard claim 2 (i.e., from 2.5% to about 4%) would now
`
`infringe claim 23 of the ’268 patent and, therefore, anticipates claim 23. See, e.g.,
`
`Polaroid Corp. v. Eastman Kodak Co., 789 F.2d 1556, 1573 (Fed. Cir. 1986)
`
`(“[T]hat which infringes if later anticipates if earlier.” (quoting Peters v. Active
`
`Mfg. Co., 129 U.S. 530 (1889)). Although Leonard claim 2 discloses a broader
`
`bioavailability range than that of claim 23, an overlapping range anticipates a
`
`claimed range unless the claimed range is “critical” to the claimed invention.
`
`Ineos USA LLC v. Berry Plastics Corp., 783 F.3d 865, 870 (Fed. Cir. 2015) (citing
`
`ClearValue, Inc. v. Pearl River Polymers, Inc., 668 F.3d 1340, 1345 (Fed. Cir.
`
`2012)). The ’268 specification provides no suggestion that the claimed range is
`
`2 Patent Owner’s assertion (POR 48) that Leonard claim 2 “does not expressly call
`
`out that zoledronic acid is the sole therapeutically active agent” is irrelevant as this
`
`is not a question of inherency. Claim 2 clearly covers such embodiments. Indeed,
`
`Leonard describes many such dosage forms. See Paper 2 (“Pet.”) at 49-52.
`
`5
`
`
`
`critical to the invention, or in any way preferable to the range disclosed in Leonard.
`
`Exh. 1005 ¶¶124-26.
`
`II.
`
`CLAIM 23 IS OBVIOUS OVER LEONARD ALONE
`
`If Leonard does not anticipate claim 23, that claim is nevertheless obvious
`
`over Leonard. Where, as here, a claimed range overlaps or lies inside ranges
`
`disclosed by the prior art, a prima facie case of obviousness exists. In re
`
`Wertheim, 541 F.2d 257 (C.C.P.A. 1976). As discussed above, Patent Owner has
`
`provided no evidence of criticality to rebut the strong prima facie case here.
`
`Patent Owner’s assertion (POR 55-56) that the bioavailability values at the
`
`lower end of the range were considered less desirable to Leonard is simply
`
`incorrect. Leonard nowhere states that bioavailability at the low end of the range
`
`should be avoided. Quite the contrary, Leonard specifically claims
`
`bioavailabilities as low as 2.5% and clearly considered such values part of the
`
`invention. Thus, it certainly cannot be said that Leonard “teaches away” from the
`
`claims of the ’268 patent. In an effort to support this argument, Patent Owner
`
`primarily relies on testimony from Petitioner’s expert Dr. Bruehl from an earlier
`
`PGR. Dr. Bruehl, however, is not an expert in bioavailability (Exh. 2022 9:17-
`
`10:11), and he did not, as Patent Owner asserts, testify as to whether a POSA
`
`would have been motivated to prepare a dosage form having a bioavailability less
`
`than 4% based on Leonard.
`
`6
`
`
`
`Dr. Wargin, on the other hand, disagrees with Patent Owner that a POSA
`
`would not have been motivated to select a dosage form having a bioavailability at
`
`the lower end of the range in Leonard. Dr. Wargin testified that a POSA would
`
`find a dosage form of zoledronic acid having a bioavailability of 2.5%
`
`advantageous over one with a bioavailability of 13% due to the potential for side
`
`effects at the higher end of the range. Exh. 1093 71:2-22; see also Exh. 1011 23:2-
`
`17 (Dr. Wargin: “having low bioavailability is not necessarily a disadvantage”).
`
`Indeed, Dr. Wargin testified that given the choice between a Leonard zoledronic
`
`acid dosage form with a bioavailability of 2.5% versus one with a bioavailability of
`
`13%, a POSA would have been motivated to use the dosage form with the lower
`
`bioavailability assuming both were effective in delivering a therapeutically
`
`effective amount of zoledronic acid. Exh. 1093 73:5-21; see also Exh. 1011 69:17-
`
`23. As discussed above, a POSA would have “certainly” considered such a dosage
`
`form effective, despite the relatively lower bioavailability. Exh. 1093 112:15-23,
`
`109:4-13.
`
`Patent Owner’s assertion that the lower end of the range of claim 2 in
`
`Leonard was less desirable is also legally irrelevant. As the Federal Circuit has
`
`explained, a “finding that the prior art as a whole suggests the desirability of a
`
`particular combination need not be supported by a finding that the prior art
`
`7
`
`
`
`suggests that the combination claimed by the patent applicant is the preferred, or
`
`most desirable, combination.” In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004);
`
`Merck & Co. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). As such,
`
`preparation of a dosage form of a zoledronate salt having a bioavailability within
`
`the range of claim 23 would have been obvious as of May 2014, even if a POSA
`
`would have believed such a form less desirable than those having a higher
`
`bioavailability.
`
`III. CLAIMS 23-30 ARE OBVIOUS OVER LEONARD, ARONHIME AND
`THE MERRION POSTER
`
`A.
`
`Claim 23 Is Anticipated by Aronhime and Is Therefore Obvious
`
`As correctly stated by Patent Owner, “the claims [of the ’268 patent] do not
`
`require formulating an oral dosage form or adding a bioavailability-enhancing
`
`agent to result in a desired bioavailability range, but instead require only that the
`
`oral dosage form have a bioavailability within the claimed range.” POR 23 n.3.
`
`Aronhime discloses such a dosage form and therefore anticipates claim 23.
`
`As discussed in the Petition, Aronhime describes fourteen different
`
`zoledronate salt forms, including eleven disodium salts, along with pharmaceutical
`
`compositions comprising those salt forms. Pet. at 49 (discussing Exh. 1035 3:10-
`
`4:30, 16:18-23). In the POR, Patent Owner produced for the first time in Exh.
`
`2026, data on one of those salt forms, zoledronate disodium tetrahydrate (Form VII
`
`in Aronhime). Exh. 1093 40:6-18. According to Dr. Wargin, this data establishes
`8
`
`
`
`that the bioavailability of Form VII in Aronhime falls within the ranges claimed in
`
`the ’268 patent:
`
`Q. So if a person of ordinary skill in the art were to
`take form VII in Aronhime --
`
`A. Uh-huh.
`
`Q. -- make an oral dosage form of it --
`
`A. Right.
`
`Q. -- and determine it[s] bioavailability, that
`bioavailability would fall within the ranges claimed in
`the ’268 patent?
`
`A. That’s true, which they did.
`
`Id. 42:2-10. Dr. Wargin also testified that the bioavailability of zoledronate
`
`disodium tetrahydrate is “dose independent” and, therefore, falls within the
`
`claimed ranges regardless of the orally administered dose. Id. 40:19-41:11. This
`
`means that having a bioavailability within the claimed ranges is an inherent
`
`property of dosage forms containing zoledronate disodium tetrahydrate, such as
`
`that described as an embodiment of Aronhime. Exh. 1035 16:20-21, 8:9-16. And,
`
`as confirmed by Dr. Wargin, Form VII of Aronhime is pure API and, therefore, by
`
`definition free of any other therapeutically active agents. Exh. 1093 124:20-
`
`125:17. Correspondingly, a pharmaceutical composition comprising Form VII
`
`would also be free of any other therapeutically active agents.
`
`9
`
`
`
`Consequently, embodiment 124 in Aronhime of a pharmaceutical
`
`composition comprising Form VII (embodiment 53) anticipates claim 23.3 At
`
`bottom, all the ’268 inventor has done is take a pharmaceutical composition of
`
`zoledronic acid in Aronhime and, through routine testing, determined its
`
`bioavailability. The discovery of a new property of a known dosage form through
`
`routine testing, however, is not inventive and does not overcome anticipation. See,
`
`e.g., Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999); see
`
`also In re Kao, 639 F.3d 1057, 1070 (Fed. Cir. 2011) (food effect not shown in
`
`prior art reference held to be inherent property of oxymorphone itself in any
`
`formulation based in part on admission of patentee).
`
`While Petitioner did not raise anticipation by Aronhime, it could not have as
`
`Petitioner was not yet privy to the data in Exh. 2026. Nevertheless, all of the bases
`
`for anticipation over Aronhime (i.e., that Aronhime teaches pharmaceutical dosage
`
`forms containing all of the known zoledronate salt forms as of May 2014) were set
`
`forth in the Petition. See Pet. at 49. Thus, Petitioner is not, if alleged by Patent
`
`3 Also, if Patent Owner attempts to argue in sur-reply that the compositions in
`
`Aronhime are limited to intravenous compositions, that is false. The background
`
`of the invention is directed to advantages regarding oral administration of the
`
`disclosed zoledronate forms. Exh. 1035 at 2-3.
`
`10
`
`
`
`Owner in sur-reply, setting forth an entirely new rationale for invalidity worthy of
`
`being excluded.
`
`Moreover, Petitioner raised Aronhime as a reference rendering claim 23
`
`obvious in combination with Leonard and the Merrion Poster and it is well settled
`
`that “anticipation is the epitome of obviousness.” In re McDaniel, 293 F.3d 1379,
`
`1385 (Fed. Cir. 2002) (quoting Connell v. Sears Roebuck & Co., 722 F.2d 1542,
`
`1548 (Fed. Cir. 1983)). Thus, claim 23 is at the very least obvious over Aronhime
`
`in combination with Leonard and/or the Merrion Poster even without the additional
`
`teachings in those references.
`
`B.
`
`Claim 23 Is Obvious Over Leonard and Aronhime
`
`Claim 23 is obvious over Aronhime in combination with Leonard. Patent
`
`Owner’s response is plainly an effort at misdirection and does not address the
`
`substance of what is taught by Leonard, i.e. a successful and reliable method of
`
`increasing the bioavailability of bisphosphonates and their salts through the use of
`
`an enhancer. Patent Owner ignores the fact that Leonard claims zoledronic acid
`
`dosage forms having a bioavailability range that overlaps with the ranges recited in
`
`the claims of the ’268 patent, and instead looks to the Leonard specification and
`
`notes (POR 52-53) that one can find up to 16 different bioavailability ranges
`
`arguing that “Petitioner has not explained why Leonard suggests a combination of
`
`a salt form of zoledronic acid and one of the particular ranges identified by
`
`11
`
`
`
`Petitioner.” As Dr. Wargin testified, however, practically speaking, a POSA does
`
`not think about combining a salt form with a theoretical bioavailability range. Exh.
`
`1093 114:5-115:1.
`
`Therefore, it is not a question of whether a POSA would have combined a
`
`specific range in Leonard with a salt from Aronhime; rather, the appropriate
`
`question as to obviousness is whether a POSA as of May 2014 would have been
`
`motivated to combine the teachings of Aronhime (i.e., improved zoledronic acid
`
`forms and compositions) with those of Leonard and/or the Merrion Poster (i.e., a
`
`method of increasing bioavailability through the use of an enhancer) with a
`
`reasonable expectation of success. The answer is yes, as discussed below.
`
`First, a POSA would have selected a zoledronate salt form in Aronhime for
`
`formulation over the free acid since a POSA would have known that “the un-
`
`ionized (free) form of weak acids and bases . . . may not be the ideal molecular
`
`form for development.” Exh. 1005 ¶143 (quoting Exh. 1084 at 704). The POSA
`
`would therefore have investigated preparing salt forms “to explore whether one of
`
`them would make a more suitable API” than the free acid and Aronhime suggests
`
`that zoledronate salts have many improved physicochemical properties, including
`
`improved dissolution, solubility, and crystallinity properties. Id.; Exh. 1035 17:19-
`
`23; 22:18-26.
`
`12
`
`
`
`Second, as Dr. Wargin admitted, “the [POSA] was motivated, as of May
`
`2014, to find ways of increasing the bioavailability of zoledronic acid dosage
`
`forms.” Exh. 1093 113:16-25. Such a method was taught by Leonard.
`
`Third, a POSA would have had a reasonable expectation of success, as
`
`clearly admitted by Dr. Wargin:
`
`Q. I’m asking whether, prior to May 2014, whether
`a person of ordinary skill in the art could have formulated
`a salt form of zoledronic acid with sodium [caprate] to
`achieve a bioavailability between 1.1 and 4 percent?
`
`A. Yes, yes.
`
`Q. And they could do so without the guidance of
`the ’268 patent?
`
`A. Yes.
`
`Id. 77:13-23 (objection omitted).
`
`Thus, to take advantage of their beneficial properties, a POSA would have
`
`been motivated to enhance the bioavailability of the pharmaceutical dosage forms
`
`containing zoledronate salts in Aronhime, including those containing the disodium
`
`salt forms, by using the method taught by Leonard. Exh. 1005 ¶146. As Dr.
`
`Wargin admitted, doing so would have been a matter of routine experimentation.
`
`Exh. 1093 75:10-23. Accordingly, claim 23 is obvious based on the combination
`
`of Leonard and Aronhime.
`
`13
`
`
`
`C.
`
`The Merrion Poster Is Prior Art
`
`The Wayback Machine archive establishes that the Merrion Poster was
`
`publicly accessible and archived on the internet as early as March 2, 2011. Exh.
`
`1094; see also Exh. 1065 (confirming that a document plainly identifiable as the
`
`Merrion Poster could be found on December 3, 2011 at
`
`http://merrionpharma.com:80/archive/portfolio/Oct2009ASCOBCPoster.pdf).
`
`Patent Owner asserts (POR 68-69) that such evidence is insufficient to show that a
`
`POSA would have found the Merrion Poster using specific and relevant search
`
`words. This assertion, however, is undercut by the fact that Patent Owner was able
`
`to locate the Merrion Poster as evidenced by its citation to the PTO as early as May
`
`2013 during prosecution of Patent Owner’s ’485 published application (Exh.
`
`2018). Exh. 1012 at 3; see also Exh. 1002 at 95. According to Patent Owner (POR
`
`13-15), a POSA is presumed to be aware of the ’485 publication, which was
`
`published prior to May 2014 and, therefore, a POSA would have been aware of the
`
`Merrion Poster as relevant prior art and would have searched for and obtained it
`
`either on the internet (as Patent Owner apparently did) or from the ’485
`
`publication’s public prosecution history. Thus, regardless of whether the Merrion
`
`Poster was publicly available prior to May 2013, it certainly was after Patent
`
`Owner submitted it to the patent office and their application was made public in
`
`May 2013 and is, therefore, unequivocally prior art.
`
`14
`
`
`
`D.
`
`Ground 8 Does Not Fail if the Merrion Poster Is Not Prior Art
`
`Patent Owner suggests, without citation to authority, that should the Board
`
`find the Merrion Poster is not prior art, that Grounds 8-9 must fail. See, e.g., POR
`
`71. However, as discussed at length above, claims 23-30 are obvious over at least
`
`Leonard and Aronhime in combination. Thus, those claims are likewise obvious
`
`over the combination of Leonard, Aronhime, and the Merrion Poster.4 To be clear,
`
`Petitioner did not rely solely on the Merrion Poster for any limitation of these
`
`claims, but merely as additional evidence of obviousness. Indeed, Petitioner
`
`repeatedly presented the Merrion Poster as an additional reference supporting the
`
`disclosure of Leonard. See, e.g., Pet. at 47 (“The Merrion Poster concerns the
`
`same dosage forms disclosed in Leonard, confirming that those dosage forms have
`
`bioavailabilities overlapping and within the ranges required by claims 23-30.”); id.
`
`at 50 (“However, should the board find that Leonard does not adequately disclose
`
`the bioavailability limitation of challenged claim 23, the Merrion Poster also
`
`describes zoledronic acid formulations having a bioavailability of from about 1.2%
`
`to about 4%.”); id. at 64 (Leonard and Merrion Poster disclosing the same
`
`limitation in claim 3). Thus, the Merrion Poster is not “the cornerstone of
`
`4 Patent Owner has not alleged that the Merrion Poster teaches away from either
`
`claims 23-30 or 3-15.
`
`15
`
`
`
`[Petitioner’s] proposed grounds” as Patent Owner asserts (POR 62); rather it is
`
`merely supplemental evidence to Leonard and not necessary for a finding of
`
`obviousness under Grounds 8 and 9.
`
`E.
`
`Claims 24-30 Are Obvious Over Leonard, Aronhime and the
`Merrion Poster
`
`Patent Owner’s assertion (POR 57-60) that dependent claims 24-29 are
`
`nonobvious over the prior art based on unexpected results is unavailing. As to
`
`unenhanced forms of zoledronic acid, Dr. Wargin testified that “it was known that
`
`the salt forms in Aronhime increased solubility over the free acid to a POSA prior
`
`to May 2014” and, therefore, a POSA “[m]ost likely” would have had a
`
`“reasonable expectation that the bioavailability of the disodium salt forms in
`
`Aronhime had a higher bioavailability” than zoledronic acid. Exh. 1093 99:20-
`
`100:9. Indeed, the prior art taught that several other bisphosphonate salt forms had
`
`bioavailabilities greater than those observed for zoledronate disodium tetrahydrate,
`
`as noted by Patent Owner. POR 36 (citing Exh. 2010 (disodium tiludronate
`
`bioavailability of 6%); Exh. 2009 (disodium etidronate bioavailability of 3%); Exh.
`
`2011 (sodium olpadronate bioavailability of 3-4%)). Patent Owner further relies
`
`on the testimony from Dr. Wilson that “every POSA understands that zoledronic
`
`acid has a similar chemical structure to other bisphosphonates and behaves the
`
`same as other bisphosphonates.” POR 75. Patent Owner does not explain why a
`
`bioavailability of 1.59-2.08% for a disodium salt form of zoledronate is unexpected
`
`16
`
`
`
`in light of higher reported bioavailabilities for other similar bisphosphonates. As
`
`such, Patent Owner’s alleged evidence of unexpected results is unpersuasive and
`
`claims 23-30 are obvious for the same reasons as claim 23, especially in the face of
`
`such a strong prima facie case.
`
`IV. CLAIMS 3-15 ARE OBVIOUS OVER LEONARD, THE MERRION
`POSTER, FOX AND LASLETT
`
`Patent Owner does not provide any additional reasons as to why claims 3-15
`
`should be found patentable over claims 23-30. Thus, for the reasons discussed
`
`above, claims 3-15 are invalid over Leonard, the Merrion Poster, Fox and Laslett.
`
`V.
`
`NO SECONDARY CONSIDERATIONS SUPPORT
`PATENTABILITY
`
`Patent Owner cites to “skepticism” of Petitioner’s experts as an objective
`
`indicia of nonobviousness. POR 74-77. However, at most the cited skepticism
`
`relates only to unenhanced zoledronic acid dosage forms, which is not what is
`
`claimed in the ’268 patent. There certainly was no skepticism in the art as of May
`
`2014 as to whether a POSA could formulate a dosage form that meets the
`
`limitations of the claims using Leonard either alone or in combination with
`
`Aronhime and the Merrion Poster, as admitted by Dr. Wargin. Exh. 1093 93:19-
`
`94:1.
`
`17
`
`
`
`VI.
`
`IF NOT OBVIOUS, CLAIMS 3-30 ARE INVALID FOR LACK OF
`ENABLEMENT
`
`Nowhere is it more apparent that the ’268 patent provides nothing over what
`
`was already taught in the prior art than in Patent Owner’s response on enablement.
`
`Instead of pointing to evidence of enablement within the specification, Patent
`
`Owner instead primarily looks to the prior art to establish enablement. However,
`
`“[i]t is the specification, not the knowledge of one skilled in the art, that must
`
`supply the novel aspects of an invention in order to constitute adequate
`
`enablement.” Genentech Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1366 (Fed. Cir.
`
`1997).
`
`Patent Owner must rely on the prior art for enablement because “[t]here is
`
`no actual data on any particular dosage form of zoledronic acid regarding
`
`bioavailability,” as conceded by Dr. Wargin. Exh. 1093 89:17-22. Despite its
`
`expert’s admissions as to the lack of data in the ’268 patent, Patent Owner
`
`nevertheless grasps for anything in the specification that could be read as actual
`
`bioavailability data by asserting (POR 26-27) that “[t]he specification, at col. 8,
`
`lines 32-33, discloses that a disodium salt form of zoledronic acid can have a
`
`bioavailability of 0.015, which equates with 1.5% bioavailability.” Dr. Wargin
`
`disagrees, testifying that a POSA would have recognized that the inventor here was
`
`18
`
`
`
`simply providing hypothetical numbers to exemplify how one could use the
`
`formula at col 8, line 25.5 Exh. 1093 129:7-130:10.
`
`Patent Owner also implies that the disclosure that the “oral bioavailability of
`
`zoledronic acid can be . . . about 1.4% to about 1.5%, about 1.5% to 1.6%”
`
`provides evidence that the inventor actually demonstrated such a bioavailability.
`
`POR 26-27. But the context of that selected citation shows that those ranges are
`
`among over two dozen ranges with endpoints as low as 0.1% to up to 10%. Exh.
`
`1001 col. 13, line 61-col. 14, line 11. Thus, just because the number 1.5% (which
`
`we know does not correspond to any actual data obtained by Patent Owner)
`
`appears somewhere in the specification does not indicate to a POSA that a dosage
`
`form with that bioavailability was actually achieved. To be sure, Dr. Wargin
`
`conceded that there is not a single statement in the specification that says that the
`
`bioavailability of the zoledronate disodium salt actually falls within any of the
`
`5 Patent Owner similarly mischaracterizes this section by asserting (POR 24) that
`
`the ’268 specification teaches that bioavailability of zoledronic acid is 1%.
`
`According to Dr. Wargin, the bioavailability of zoledronic acid is not 1%, but “less
`
`than 1%.” Exh. 1093 113:2-20. For this reason, one cannot read the ’268 patent
`
`teaching that a 200% increase in bioavailability of a zoledronic acid form
`
`correlates with 3%. Exh. 1005 ¶71.
`
`19
`
`
`
`claimed ranges. Exh. 1093 89:24-90:3. The specification simply states that the
`
`bioavailability “may be enhanced by orally administering the zoledronic acid in the
`
`disodium salt form.” E.g., Exh. 1001 col. 7, ll. 65-67.
`
`Although Patent Owner has submitted evidence that a single zoledronate salt
`
`form has a bioavailability within the claimed range, this is insufficient evidence to
`
`enable the full scope of the claims. Claims 1-22 broadly claim dosage forms
`
`comprising any form of zoledronic acid while claims 23 and 30 cover any salt form
`
`with or without bioavailability enhancers. Because the claims are so broad, it
`
`would require undue experimentation for a POSA to practice the full scope of the
`
`claims, given the lack of guidance in the specification.
`
`The ’268 patent does not identify any particular disodium salt form having
`
`the recited bioavailability or provide any instructions for how to make such a
`
`disodium salt form and a POSA would not have known which, if any, of the known
`
`disodium salt forms to use. Exh. 1005 ¶70. Patent Owner again looks outside the
`
`’268 specification to the ’669 application to suggest that the POSA would have
`
`known that the inventor had discovered that zoledronate disodium tetrahydrate had
`
`a bioavailability within the claimed ranges. POR 16-17, 31. As discussed in the
`
`Petition at 25-26, a POSA would have made no such conclusion. Dr. Wargin
`
`agrees, conceding that “a [POSA] cannot look at Example 7 and say the absolute
`
`bioavailability of the disodium salt of zoledronic acid is between 1.1 and 4 percent
`
`20
`
`
`
`in humans.” Exh. 1011 107:1-5; see also Exh. 1093 128:25-129:6. Dr. Wargin
`
`further admitted that a POSA in 2014 would not believe bioavailability data in
`
`dogs correlates well to humans and that if a POSA were to determine the
`
`bioavailability of a particular zoledronic acid dosage form was between 1.1 and
`
`2.3% in dogs, it is “probably unlikely” that a POSA would get the same number in
`
`a human study. Exh. 1011 34:4-19, 35:1-10.
`
`Yet, even if the ’669 application would have led a POSA to test the
`
`disodium salt forms in Aronhime to find a dosage form that meets the limitations
`
`of the claims, Patent Owner’s own evidence of experimentation demonstrates that
`
`such experimentation is undue. Dr. Wargin testified that in order for a POSA to
`
`actually practice the claims of the ’268 patent, it would requi
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
