throbber
UNITED STATES PATENT AND TRADEMARK OFFICEUNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARDBEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`PURDUE PHARMA L.P.PURDUE PHARMA L.P.
`
`Petitioner,Petitioner,
`
`
`vvv.v.
`
`DEPOMED, INC.DEPOMED, INC.
`
`Patent Owner.Patent Owner.
`
`Case IPR2014-00377 (Patent 6,635,280)
`Case IPR2014-00377 (Patent 6,635,280)
`Case IPR2014-00378 (Patent 6,340,475)
`Case IPR2014-00378 (Patent 6,340,475)
`Case IPR2014-00379 (Patent 6,340,475)
`Case IPR2014-00379 (Patent 6,340,475)
`
`PETITIONER’S DEMONSTRATIVES FOR
`PETITIONER’S DEMONSTRATIVES FOR
`CONSOLIDATED ORAL HEARING
`CONSOLIDATED ORAL HEARING
`March 19, 2015
`March 19, 2015
`Franklin, Obermann, Hulse, Administrative Patent Judges
`Franklin, Obermann, Hulse, Administrative Patent Judges
`
`1
`
`

`
`
`
`Inter Partes Review instituted on the following groundsInter Partes Review instituted on the following grounds
`
`Claims
`
`Grounds for Review
`IPR2014-00377 (US Patent No. 6,635,280)
`1, 8, 9, 13-15, 45, and 46
`Obvious over Baveja,’837 patent, and ’548 patent
`10
`Obvious over Baveja, Kim, and ’837 patent
`43
`Obvious over Baveja, ’837 patent, and Colombo
`IPR2014-00378 (US Patent No. 6,340,475)
`Obvious over Baveja, ’837 patent, and ’548 patent
`1, 8, 9, 13-15, and 61
`
`Obvious over Baveja, Kim, ’837 patent, and ’548 patentObvious over Baveja, Kim, 837 patent, and 548 patent
`
`1010
`1, 8, 9, 13, 14, 61, and 62 Obvious over Colombo, ’837 patent, and ’548 patent
`IPR2014-00379 (US Patent No. 6,340,475)
`
`43 54 55 57 5843, 54, 55, 57, 58, and 66d 66
`
`tt d b ’803iA tiAnticipated by ’803 patentt
`
`
`
`
`
`Obvious over ’837 patent, Baveja, and Colombo
`43, 57, 58, and 66
`54 and 55
`Obvious over ’837 patent, Baveja, Colombo, and ’125 patent
`
`Source: IPR2014-00377, Paper 9; IPR2014-378, Paper 10; IPR2014-00379, Paper 9
`.
`2
`
`

`
`PO claims well-known formulations and methods of treatment in terms
`of their known properties
`
`Claim 1 contains two composition elements (highlighted).
`The remaining portion is a list of properties of the claimed
`polymer matrix dosage form
`polymer matrix dosage form.
`
`’280 Patent
`
`Source: IPR2014-00377, Exh. 1001, ’280 patent claim 1; Pet. 3
`.
`
`3
`
`

`
`
`PO claims well-known formulations and methods of treatment in terms PO claims well-known formulations and methods of treatment in terms
`
`of their known properties (cont.)of their known properties (cont.)
`
`Claim 43 contains three basic elements (highlighted). The
`remaining portion is a list of properties of the claimed
`polymer matrix dosage form.
`polymer matrix dosage form
`
`’280 Patent
`
`Source: IPR2014-00377, Exh. 1001, ’280 patent, claim 43; Pet. 3-4
`.
`4
`
`

`
`
`
`KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727 (2007)KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727 (2007)
`
` A combination of familiar elements according to known methods g
`
`
`and yielding predictable results is obvious.
`
` A simple arrangement of old elements, each performing the same
`
`function is obviousfunction, is obvious.
`
` When a design need has a finite number of identified,
`
`predictable solutions, and pursuit of these known options is within p , p p
`
`
`
`his or her technical grasp, which leads to success, it is the product
`of ordinary skill and common sense, not invention.
`
`A fi di A finding of obviousness is warranted where a combination of f b i i t d h bi ti f
`
`
`
`
`
`
`
`elements or a purported advance would have occurred in the
`ordinary course of development.
`
`Source: KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1739-42 (2007); IPR2014-00377, Pet. 33-34; IPR2014-
`00378, Pet. 29; IPR2014-00379, Pet. 25-26
`.
`
`5
`
`

`
`
`The formulations claimed in the ’280 and ’475 patents The formulations claimed in the ’280 and ’475 patents
`
`consist of known APIs and excipients (Pet. 7)consist of known APIs and excipients (Pet. 7)
`
` As of June 1997, it was known that:
`
`– Hydrophilic, swellable polymers control the release of high solubilityHydrophilic, swellable polymers control the release of high solubility
`drugs. (Pet. 34)
`– Adjusting the concentration or molecular weight of polymers (e.g.,
`
`HPMC) alters the rate of drug release (Pet 43)HPMC) alters the rate of drug release. (Pet. 43)
`– Administering oral dosage forms during the fed mode promotes
`retention in the stomach. (Pet. 34)
`– Increasing the viscosity of HPMC (based on grade) or the
`concentration (by altering the drug-to-polymer weight ratio)
`strengthens the matrix, resulting in a dosage form that would remain
`
`i tllh iphysically intact over the dosing period. (Pet. 36-37)t th d i i d (P t 36 37)
`
`
`
`
`
`
`Source: IPR2014-00377
`.
`
`6
`
`

`
`
`The formulations claimed in the ’280 and ’475 patents are prepared The formulations claimed in the ’280 and ’475 patents are prepared
`
`according to conventional techniquesaccording to conventional techniques
`
`’280 Patent
`
`Source: IPR2014-00377, Exh. 1072, 173:6-9; Reply 3
`.
`
`7
`
`

`
`
`The only limitation disputed in PO’s Response as absent in the prior art The only limitation disputed in PO’s Response as absent in the prior art
`
`combination is “dissolution and diffusion” combination is “dissolution and diffusion”
`
`Claim 1 Limitations
`
`“Controlled-release oral drug dosage form” immersion (Not addressed in
`PO’s Responses)
`
`
`
`
`
`
`
`
`
`
`l“f“for releasing a drug whose solubility in water is greater than one part by i d h l bilit i t i t th t b
`
`
`weight of said drug in ten parts by weight of water” immersion (377 Resp.
`25-28; Reply 6; 378 Resp. 25-26; Reply 6)
`“a solid polymeric matrix…at a weight ratio of drug to polymer of from
`about 15:85 to about 80:20” (Not addressed in PO’s Responses)
`
`“Swollen…dimensionally unrestricted…to promote retention…during fed
`mode (’280)” or “Swells…to promote retention…during fed mode (’475)”
`(377 Resp. 37-39; Reply 7-8; 378 Resp. 42-43; Reply 10)
`
`“Fed mode” or “Gastric fluid” (377 Resp. 28-29; Reply 11; 378 Resp. 42-
`
`43 R l 11)43; Reply 11)
`
`Release by “dissolution and diffusion” (PO’s construction) (377 Resp. 30-
`32; Reply 5-7; 378 Resp. 29-31; Reply 10-11)
`“retains at least about 40%” one hour after such immersion (Not
`
`addressed in PO’s Responses)addressed in PO s Responses)
`“Releases substantially all of said drug after immersion (’280)” or
`“Releases substantially all of said drug within about eight hours after
`immersion (’475)” (377 Resp. 39-40; Reply 8; 378 Resp. 36-37; Reply
`11-12)
`
`“Remains substantially intact until [substantially (’280)] all of said drug is
`released” (377 Resp. 35-37; Reply 7; 378 Resp. 34-37; Reply 12)
`Source: IPR2014-00377; IPR2014-00378
`.
`
`8
`
`Baveja, ’837, ’548
`(’475/’280)
`
`Colombo, ’837, ’548
`(’475)
`
`
`
`
`
`
`
`
`
`
`
`x
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`x
`
`
`
`
`
`
`
`

`
`
`The only limitation disputed in PO’s Response as absent in the prior art The only limitation disputed in PO’s Response as absent in the prior art
`
`combination is “dissolution and diffusion”combination is “dissolution and diffusion”
`
`Claim 43 Limitations
`
`“A method of administering to a subject a drug that is therapeutic to said subject when absorbed
`in the stomach where said drug has at least one ionized group in the pH range 5 through 8” (377
`
`
`d i PO’ R30 36) (N t dd35 40 379 RRResp. 35-40; 379 Resp. 30-36) (Not addressed in PO’s Responses))
`
`
`
`“Solid polymeric matrix…at a weight ratio of drug to polymer of from about 0.01:99.99 to about
`80:20” (Not addressed in PO’s Responses)
`
`“Swollen…dimensionally unrestricted…to promote retention…during fed mode (’280)” or
`
`to promote retention during fed mode (’475)” (377 Resp 37 39; Reply 7 8; 379 Resp“SwellsSwells…to promote retention…during fed mode ( 475) (377 Resp. 37-39; Reply 7-8; 379 Resp.
`
`30-36; Reply 7-8)
`
`“Fed mode” or “Gastric fluid” (377 Resp. 35-37; Reply 7-8; 379 Resp. 33-34; Reply 9-10)
`
`“Dissolving…and either erosion of said matrix or diffusion” (PO’s construction) (377 Resp. 30-32;
`
`30 32 R l 7 9)R l 5 7 379 RReply 5-7; 379 Resp. 30-32; Reply 7-9)
`
`“retains at least about 40%” one hour after such immersion (Not addressed in PO’s Responses)
`
`“Releases substantially all of said drug after immersion (’280)” or “Releases substantially all of
`said drug within about ten hours after immersion (’475)” (377 Resp. 39-40; Reply 8; 379 Resp.
`33; Reply 8-9)
`
`“remains substantially intact until all of said drug is released” (377 Resp. 35-37; Reply 7; 379
`Resp. 35-36; Reply 10)
`
`“Extending the release rate…while releasing substantially all” (379 Resp. 34-35; Reply 10)
`
`Source: IPR2014-00377; IPR2014-00379
`.
`
`9
`
`Baveja, Colombo, ’837
`(’475/’280)
`
`
`
`
`
`
`
`
`
`
`
`x
`
`
`
`
`
`
`
`
`
`

`
`
`PO’s expert admitted that all of the elements of the challenged claims PO’s expert admitted that all of the elements of the challenged claims
`
`are in the prior art are in the prior art
`
`THE WITNESS: I think, just as we said about all the
`elements of the claim, those elements are known in the
`art and understood by the skilled artisan. What is unique
`to the claim is the unique combination of these elements.
`
`. . .
`
`Deposition Transcript of
`Harold B. Hopfenberg
`
`THE WITNESS: I believe that everything in here, including
`the claim element we're speaking about and
`understanding thereof, is -- I mean, these fundamental
`understanding thereof is -- I mean these fundamental
`issues of swelling, dissolution, diffusion, erosion, et
`cetera are known in the art.
`
`.
`
`Source: IPR2014-00377, Exh. 1072, 396:18-22, 56:18-22; Reply 3
`10
`
`

`
`
`PO’s expert admitted that all of the elements of the challenged claims PO’s expert admitted that all of the elements of the challenged claims
`
`are in the prior art (cont.)are in the prior art (cont.)
`
`Q.
`
`A.
`
`Q.
`
`Are you aware of any polymer described in
`
`those patents that wasn't previously known in p p y
`
`
`the art?
`
`I don't believe so.
`
`. . .
`
`And Depomed didn't develop a new polymer
`that changed the rate of diffusion of drug,
`correct?
`
`
`
`AA.
`
`
`
`Not to my knowledgeNot to my knowledge.
`
`Deposition Transcript of
`Harold B. Hopfenberg
`
`.
`
`Source: IPR2014-00377, Exh. 1072, 41:8-11, 97:7-10; Reply 3
`11
`
`

`
`
`
`The parties’ claim construction dispute: “dissolution and diffusion”The parties’ claim construction dispute: “dissolution and diffusion”
`
`Purdue’s Construction
`
`PO’s Construction
`
`Plain and ordinary meaning:
`
`“dissolution of the drug in the matrix
`followed by diffusion of the drug out of
`the matrix.”
`
`PO construes “dissolution and
`diffusion” as the 32-word phrase:
`
`“rapid dissolution of the drug, followed
`by slow diffusion of the drug out of the
`water swollen matrix, such that the
`
`drug is released at a rate controlled bydrug is released at a rate controlled by
`the rate of diffusion.”
`
`Source: IPR2014-00377, Exh. 1066, 30:14-17; Reply 1
`.
`
`12
`
`Source: IPR2014-00377; Resp. 16-18
`
`

`
`
`
`PO’s construction is not supported by the claim languagePO’s construction is not supported by the claim language
`
` Claim 1 recites:
`“releases said drug into gastric fluid by the dissolution and diffusion of– releases said drug into gastric fluid by the dissolution and diffusion of
`
`said drug out of said matrix by said gastric fluid”
`
` Does not require: Does not require:
`
`– The rate of release to be controlled by diffusion alone;
`
`– Diffusion or any other release mechanism to be the rate controlling y g
`step;
`– A particular “order” drug release pattern (i.e., first-order or zero-order).
`
`
`
`Source: IPR2014-00377, Exh. 1001, ’280 patent claim 1; Reply 4
`.
`13
`
`

`
`PO’s construction is not supported by the ’280/’475 patent specification
`
`The ’280/’475 patent specification teaches that drug release
`depends on factors other than diffusion (e.g., swelling and
`
`drug dissolution)drug dissolution).
`
`’280 Patent
`
`(Exh. 1001, Abstract)
`
`(Exh. 1001, 6:18-23)
`
`Source: IPR2014-00377, Reply 11
`.
`
`14
`
`

`
`
`Inventor Louie-Helm agreed that controlled release of a highly soluble Inventor Louie-Helm agreed that controlled release of a highly soluble
`
`drug indicates that drug release is primarily by diffusiondrug indicates that drug release is primarily by diffusion
`
`Deposition Transcript of
`Jenny Louie-Helm
`
`Q. You state, "by controlled diffusion from a gastric retentive
`polymeric matrix in tablet form." How did you go about
`determining whether or not it was controlled diffusion?
`A. Metformin is considered a highly soluble drug, and,
`basically, outside of a barrier membrane type control mechanism
`you're really looking at diffusional release.
`Q. So based on the solubility of metformin, you determined that it y , y
`
`was controlled diffusion?
`
`
`
`. . .
`THE WITNESS: Based on the solubility of metformin, we
`THE WITNESS: Based on the solubility of metformin we
`determined we had -- for our technology, which was a matrix-
`based technology -- it would be by diffusion, yes.
`. . .
`A. Well, like I mentioned before, with high-solubility compounds,
`if you want a controlled-release dosage form, you're really
`looking at a diffusional-type matrix, whether, you know, it's
`diffusion from the matrix or diffusion through like a barrier
`
`membranemembrane.
`
`.
`
`Source: IPR2014-00377, Exh. 1079, 51:12-52:1, 57:5-24; Reply 6
`15
`
`

`
`
`PO admits that controlled release of a highly soluble drug indicates that PO admits that controlled release of a highly soluble drug indicates that
`
`drug release is by diffusion drug release is by diffusion
`
`“Because highly-soluble drugs dissolve rapidly in
`the water-swollen matrix upon immersion of the
`
`dosage form in gastric fluid these dosage formsdosage form in gastric fluid, these dosage forms
`comprising highly soluble drugs would release
`drug too rapidly to be therapeutically effective
`
`‘controlled-released’ dosage forms unlesscontrolled-released dosage forms unless
`diffusion of drug out of the matrix is sufficiently
`slow compared with the overall rate of dissolution
`
`of drug in the swollen matrix ”of drug in the swollen matrix.
`
`Source: IPR2014-00377, Resp. 16
`.
`
`16
`
`

`
`
`PO’s expert admitted that diffusion occurs in the prior art PO’s expert admitted that diffusion occurs in the prior art
`
`controlled release systemscontrolled release systems
`
`Q. But you are here to answer my questions, which at this
`point are to assume that Purdue doesn't agree with your
`construction, that the claims don't require that diffusion
`be the rate-limiting step. If it's not required to be the
`rate-limiting step, would you agree that the prior art
`
`discloses release by diffusion?discloses release by diffusion?
`
`Deposition Transcript of
`Harold B. Hopfenberg
`
`A. You mean that diffusion is involved in the mechanism of
`release?
`
`Q. Yes.
`
`A. Diffusion would be involved in the mechanism of
`
`lrelease, I think in all those systems, except for the I thi k i ll th t t f th
`
`
`
`
`
`case where you have so rapidly eroded that -- as soon as
`you erode, you eliminate the material.
`
`.
`
`Source: IPR2014-00377, Exh. 1072, 62:9-23; Reply 3
`17
`
`

`
`
`PO’s expert’s opinion regarding PO’s expert’s opinion regarding
`
`the plain and ordinary meaning of “diffusion”the plain and ordinary meaning of “diffusion”
`
`Q. Okay. Can you tell me what your opinion is as to what the
`
`plain and ordinary meaning of diffusion is? And, p a a d o d a y ea g o d us o s d,
`
`
`
`
`again, outside the scope of the patent, outside the scope
`of the specification of the claims, just the general
`
`meaning, but still in the pharmaceutical context inmeaning, but still in the pharmaceutical context in
`pharmaceutical formulations.
`
`Deposition Transcript of
`Harold B. Hopfenberg
`
`. . .
`
`THE WITNESS: Certainly. Diffusion is a process of a specific
`molecule that is being transported through another phase
`
`ifor, if you will, a surrounding solvent, wherein the resulting ill di l t h i th lti
`
`
`
`
`
`
`
`
`transport is a consequence of an imposed concentration
`gradient.
`
`.
`
`Source: IPR2014-00377, Exh. 1072, 77:8-21; Reply 1-2
`18
`
`

`
`
`PO’s construction is not supported by Endo Pharmaceuticals Inc. v. PO’s construction is not supported by Endo Pharmaceuticals Inc. v.
`
`Depomed, Inc., IPR2014-00656, Paper 12 (P.T.A.B. Sept. 29, 2014)Depomed, Inc., IPR2014-00656, Paper 12 (P.T.A.B. Sept. 29, 2014)
`
` This panel determined
`
`“[n]othing in claim 1 or claim 43 requires the drug
`
`lrelease to be ‘primarily’ by diffusion or erosion… we t b ‘ i il ’ b diff i i
`
`
`
`
`
`
`decline to import limitations from the Specification
`when applying the broadest reasonable construction.
`This is particularly true in light of claim 43, which
`
`allows for drug release by erosion or diffusion ”allows for drug release by erosion or diffusion.
`Endo, Paper 12 at 9.
`
` Accordingly, the Board construed the claims “according to their
`plain and ordinary meaning and decline[d] to import any
`requirement that the drug release occur ‘primarily’ by diffusion in
`claim 1, or by ‘rate-controlling’ erosion or diffusion in claim 43.” Id.
`at 10.
`
`Source: IPR2014-00377, Reply 1
`.
`
`19
`
`

`
`
`
`Baveja does not teach away from the claimed subject matterBaveja does not teach away from the claimed subject matter
`
` A reference “teaches away” when it “suggests that the line of
`
`development flowing from the reference’s disclosure is unlikely to be p g y
`
`
`productive of the result sought by the applicant.” Santarus, Inc. v.
`Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012). (Reply 4)
`
`B Baveja teaches that a disadvantage of hydrophilic swellable j t h th t di d t f h d hili ll bl
`
`
`
`
`
`
`
`
`
`systems is that “zero-order release is not generally observed.”
`(Reply 4)
`
` That statement does not teach away from the claimed invention
`because:
`
`– The claimed invention is not directed to “zero order release.” (Reply 4)( y )
`
`– The conventional hydrophilic swellable polymer systems (Figs. 1-3) produced: (1)
`controlled release; (2) by diffusion; and (3) without significant erosion.
`
`Source: IPR2014-00377, Reply 4-6
`.
`
`20
`
`

`
`Baveja explicitly discloses release by “dissolution and diffusion”
`
` Table 1 of Baveja reports n values, “the diffusional release
`exponent indicative of mechanism of release.” (Exh. 1008, 41-42)
`
`Source: IPR2014-00377, Exh. 1008, 41-42; Reply 4-5
`.
`
`21
`
`

`
`
`
`Baveja teaches the claimed release in “gastric fluid”Baveja teaches the claimed release in “gastric fluid”
`
` The 1:2 dosage form retained at least 40% of the drug within one hour and
`released at least 80% of the drug in diluted HCl pH 3.0. (Pet. 17-18)
`
` HCl pH 3 0 is a suitable model for SGF In PO’s words the use of diluted HCl pH 3.0 is a suitable model for SGF. In PO s words, the use of diluted
`
`HCl pH 3.0 “demonstrates the intent to mimic administration of a tablet
`formulated to pass from the stomach (which has a low pH) to the small
`intestine (which has a higher pH).” (Resp. 48)
`
` PO’s Expert, Dr. Hopfenberg, admitted that the pH of gastric fluid in the fed
`mode is as high as 4.5. (Exh. 1072, 206:24-207:3; Reply 11-12)
`
`(Exh. 1008, Fig. 1; Pet. 18)
`
`Source: IPR2014-00377
`.
`
`22
`
`

`
`
`Baveja’s formulations swell in a manner that Baveja’s formulations swell in a manner that
`
`promotes gastric retention during the fed modepromotes gastric retention during the fed mode
`
` Baveja’s dosage forms are 11 mm in diameter prior to swelling.
`
`(Pet. 13) ( )
`
`
` The ’475 and ’280 patents teach that dosage forms that swell to a
`size of 10 mm will promote gastric retention during the fed mode.
`
`(E h 1001 11 65 12 2 P t 11)(Exh. 1001, 11:65-12:2; Pet. 11)
`
` Figs. 1-3 teach a dosage form displaying an “increase in
`
`diffusional path length” over time (Exh. 1005, p. 41) indicating that p g ( , p ) g
`
`
`
`
`
`the dosage forms undergo minimal erosion and continuous swelling.
`(Reply 7)
`
`Source: IPR2014-00378
`.
`
`23
`
`

`
`
`Alprenolol HCl:HPMC, 1:2 and 1:3 tablets remained substantially intact Alprenolol HCl:HPMC, 1:2 and 1:3 tablets remained substantially intact
`
`after dissolution testing in gastric fluidafter dissolution testing in gastric fluid
`
` Dr. Kinam Park tested two formulations disclosed in Baveja:
`– Tablets containing either Alprenolol Hydrochloride:HPMC (1:2) or Alprenolol
`Hydrochloride:HPMC (1:3) were compressed at 300 psi. Each was 11 mm in
`
`didiameter. (Exh. 1015, pp. 2, 11)t (E h 1015 2 11)
`
`
`
`Images taken after all of the drug was released show they did not break apart into
`fragments and were firm to the touch.
` On average, the tablets swelled to more than 4 times their original unswelled volume.
`
`
`
`Fig. 5B
`
`Fig. 5C
`
`Source: IPR2014-00378, Exh. 1015, Figs. 2, 5B-C; Pet. 16-18
`.
`
`24
`
`

`
`
`
`Dr. Park’s preparation of Baveja’s formulationsDr. Park’s preparation of Baveja’s formulations
`
` Dr. Park prepared the Baveja tablets using techniques well known to
`a POSA.
`
`– Dr. Park used the same type of manual tablet press as used in Baveja and yp p j
`
`chose a compression force based on his knowledge as a POSA.
`– Tablet thickness is a function of the weight of the tablet in combination with
`its diameter, both of which were disclosed in Baveja.
`
`
`
` Dr. Park used “Methocel K4M Premium” HPMC having the same
`chemical composition and viscosity as the HPMC disclosed in
`Baveja.
`
`Baveja
`
`Declaration of Kinam Park
`
` “Methocel K4M Premium (HPMC) Methocel K4M Premium (HPMC) …
`
`
`received as gift samples from…Colorcon
`Ltd….” (Exh. 1008, p. 40)
`
`“The two formulations tested made exactly The two formulations tested, made exactly
`
`according to the methods described in
`Baveja, contained … Methocel K4M
`Premium (HPMC)… [Dow Chemical]” (Exh.
`
`1020 ¶¶ 14 18) 1020 ¶¶ 14, 18)
`
`Source: IPR2014-00378, Exh. 1015, pp. 2, 11; Request for Rehearing 3-9
`.
`25
`
`

`
`Colombo teaches release by “dissolution and diffusion”
`
`(Exh. 1006, p. 43; Pet. 25)
`(Exh. 1006, p. 43; Pet. 25)
`
` PO argues that Colombo’s focus was on “seeking to control drug release by swelling
`rather than …by diffusion” (Resp. 23) or by polymer relaxation (Resp. 41).
`
` PO’s argument is based on a flawed claim construction requiring that “drug is released
`at a rate controlled by the rate of diffusion.”
`–
`The ’280/475 patents do not exclude release of drug by swelling. This is supported by the
`
`ttpatent specification, stating “[t]he swelling matrix … reduces the drug release rate. This ifi ti t ti “[t]h lli t i d th d l t Thi
`
`
`
`
`
`
`
`
`
`
`
`
`process, together with diffusion . . . results in … controlled delivery rate of the drug ….”
`(Exh. 1001, Abstract).
`
`Source: IPR2014-00378, Reply 10-11
`.
`
`26
`
`

`
`
`Even under PO’s flawed claim construction, Colombo teaches that drug Even under PO’s flawed claim construction, Colombo teaches that drug
`
`is released from Case 0 by “dissolution and diffusion”is released from Case 0 by “dissolution and diffusion”
`
`Source: IPR2014-00379, Exh. 1014, Fig. 5, Fig. 6; Pet. 31
`.
`
`27
`
`

`
`
`
`Colombo teaches the “releases substantially all” limitation Colombo teaches the “releases substantially all” limitation
`
` Fig. 5 indicates that 70% is released by about three hours
`
`– Thus, it would have been obvious to a POSA reading ColomboThus, it would have been obvious to a POSA reading Colombo
`that Case 0 (or a slightly modified formulation) would release at
`least 80% of the drug within about eight hours. (Reply 12)
`
`(Exh. 1009, p. 46)
`
`Source: IPR2014-00377
`.
`
`28
`
`

`
`
`
`The “gastric fluid” limitation is obvious The “gastric fluid” limitation is obvious
`
`Colombo’s formulations would perform in substantially the
`same way in deionized water and in SGF.
`
`Q If one of the prior art references discloses release of drugQ. If one of the prior art references discloses release of drug
`
`in water, does that tell me how the drug is going to
`release in gastric fluid?
`
`
`
`MS EE ObjMS. LEE: Objection to form.i f
`
`
`
`
`
`Deposition Transcript of
`Harold B. Hopfenberg
`
`THE WITNESS: So the test you're talking about is doing a
`p
`p
`classical so-called release profile or dissolution profile,
`would there be significant differences between them.
`
`BY Mr. LAROSA:
`
`Q. Right.
`
`A. There could be differences, but I don't believe they would
`
`be significantbe significant.
`
`.
`
`Source: IPR2014-00378, Exh. 1072, 73:24-74:11; Exh. 1066, 179:17-180:20; Reply 11
`29
`
`

`
`
`Colombo teaches the “swollen…in a dimensionally unrestricted Colombo teaches the “swollen…in a dimensionally unrestricted
`
`manner… to promote retention” limitationmanner… to promote retention” limitation
`
` PO ignores Colombo’s statement that “[v]ery quickly (after 15 min) the swelling of
`the matrix moves both in axial and radial directions.” (Exh. 1009, p. 44). The
`
`claims do not contain a temporal requirement for swelling in a dimensionally g y
`
`unrestricted manner. (Reply 11)
`
`
`
`Figs. 1-4 show that the tablets continuously swell in diameter, thickness and
`volume over the course of six hours and remain substantially intact. (Exh. 1009, p.
`43-44; Pet. 23)
`
`Source: IPR2014-00377
`.
`
`30
`
`

`
`The ’837 patent explicitly teaches release by “dissolution and diffusion”
`
`The ’837 patent explicitly discloses controlled release of high solubility
`drugs. (Exh. 1010, 3:50, 4:28, 10:10, 12:22; Reply 6)
`
`PO d itPO admits in its Response that: “Because highly soluble drugs dissolve i it R th t “B hi hl l bl d di l
`
`
`
`
`
`
`
`
`rapidly in the water swollen matrix…these dosage forms comprising highly
`soluble drugs would release drug too rapidly to be therapeutically effective
`controlled release dosage forms unless diffusion of drug out of the matrix is
`sufficiently slow compared with the overall rate of dissolution of drug in the
`ffi
`i
`tl
`l
`d ith th
`ll
`t
`f di
`l ti
`f d
`i
`th
`swollen matrix.” (Resp. 16)
`
`’837 Patent
`
`
`
`
`
`t R l 6)(E h 1010 Ab t(Exh. 1010, Abstract; Reply 6)
`
`Source: IPR2014-00378
`.
`
`31
`
`(Exh. 1010, 12:20-34; Reply 6; Pet. 39-40)
`
`

`
`
`The ’837 patent does not “teach away” from the “releases substantially The ’837 patent does not “teach away” from the “releases substantially
`
`all” limitationall” limitation
`
`– The ’837 patent does not “teach away” from this limitation due to the
`disclosure of low solubility drugs. (Reply 8)
`
`
`
`’837 Patent
`There is no requirement that a “particular combination must be [] preferred…in order
`to provide motivation for the current invention.” In re Fulton, 391 F.3d 1195, 1200
`(Fed. Cir. 2004). (Reply 8)
`
`
`
`
`
`“A reference does not teach away . . . if it . . . does not ‘criticize, discredit, or otherwise
`discourage’ investigation into the invention claimed.” Galderma Laboratories, L.P. v.
`Tolmar, Inc., 2013 WL 6483704, 6 (Fed. Cir. Dec. 11, 2013). (Pet. 39-40)
`
`“A teaching that a composition may be optimal or standard does not criticize, discredit,
`or otherwise discourage investigation into other compositions.” Id. (Pet. 39-40)
`
`Source: IPR2014-00378
`.
`
`32
`
`

`
`
`
`The ’837 patent teaches controlled release of high solubility drugsThe ’837 patent teaches controlled release of high solubility drugs
`
` The ’837 patent teaches that “[n]ormally the solubility of the drug The 837 patent teaches that [n]ormally, the solubility of the drug
`
`(measured in water at 37° C.) will be in the range of 0.01% to about 35%
`by weight…” (Exh. 1010, 2:35-37; Reply 8)
`
`’837 Patent
`The ’837 patent encourages the use of high solubility drugs, with specific examples of
`Th ’837
`t
`t
`th
`f hi h
`l bilit d
`ith
`ifi
`l
`f
`
`formulations including drugs such as ranitidine and diltiazem. (Exh. 1010, 3:50, 4:28,
`10:7-14, 12:20-34; Exh. 1003; Reply 6)
`
`
`
`tTh ’837The ’837 patent teaches that because alkyl-substituted cellulose “dissolve[s] very t t h th t b lk l b tit t d ll l “di l [ ]
`
`
`
`
`
`
`
`
`
`
`
`
`slowly in gastric fluid, the particles maintain their integrity over at least a substantial
`portion (i.e., at least about 90% and preferably over 100% of the intended dosing
`period).” (Exh. 1010, 4:42-46; Pet. 34)
`
`Source: IPR2014-00378
`.
`
`33
`
`

`
`
`
`The ’548 patent teaches the “dissolution and diffusion” limitationThe ’548 patent teaches the “dissolution and diffusion” limitation
`
` An object of the ’548 invention is to release drug “over a
`prolonged period of time.” (Exh. 1017, 2:46-56; Reply 6-7)
`
`’548 Patent
`
` The ’548 patent discloses the use of high solubility drugs.
`(Exh. 1017, 6:3, 6:39-40, 8:47, and 5:65-6:11; Pet. 5)
`
` A POSA understands that prolonged release of highly solubleA POSA understands that prolonged release of highly soluble
`
`drugs occurs by “dissolution and diffusion.” (Reply 6-7)
`
`Source: IPR2014-00377
`.
`
`34
`
`

`
`
`
`The ’548 patent teaches the “swollen…to promote retention” limitationThe ’548 patent teaches the “swollen…to promote retention” limitation
`
`The ’548 patent teaches that the “use of cellulose ethers,
`especially the high number average molecular wt cellulose
`ethers…swell extensively when hydrated…” (Exh. 1017, 11:23-
`
`25; Pet 41)25; Pet. 41).
`The ’548 dosage forms provide “gastric retention over the drug
`releasing life time of the dosage form.” (Exh. 1017, 10:65-68,
`11:23-25; Pet. 41).)
`
`
`’548 Patent
`
`(Exh. 1017, 10:65-68; Pet. 41)
`
`Source: IPR2014-00377
`.
`
`35
`
`

`
`The ’548 patent teaches the “substantially intact” limitation
`
`The ’548 patent teaches a dosage form that “avoids a premature
`disintegration,” and “exhibit[s] better mechanical integrity.” (Exh. 1017,
`3:1-4, 10:68-11:7; Reply 7)
`
` Addresses problems with prior art tablets that “prematurely” break up and
`“undergo substantial disintegration in a short time span, usually less than
`eight hours.” (Exh. 1017, 1:35-44; Reply 7)
`
`’548 Patent
`
`Discloses adjusting the rate of erosion with use of low and high
`molecular weight cellulose ethers in order to achieve “better mechanical
`integrity.” (Exh. 1017, 11:5-7; Reply 6)
`
`(Exh. 1017, 11:3-11; Reply 7)
`
`Source: IPR2014-00377
`.
`
`36
`
`(Exh. 1017, 1:29-44; Reply 7)
`
`

`
`
`PO only disputes disclosure of the “substantially intact” and the PO only disputes disclosure of the “substantially intact” and the
`
`“swells…to promote retention” limitations in the ’803 patent“swells…to promote retention” limitations in the ’803 patent
`
`Claim 43 Limitations
`“A method of administering to a subject a drug that is therapeutic to said subject
`when absorbed in the stomach where said drug has at least one ionized group in the
`
`pH range 5 through 8”pH range 5 through 8
`“Solid polymeric matrix…at a weight ratio of drug to polymer of from about
`0.01:99.99 to about 80:20”
`
`’803 Patent
`
`
`
`
`
`xx
`
`
`
`
`
`
`
`
`x
`
`
`
`“Swells…to promote retention…during fed mode (’475)”p g ( )
`
`“Fed mode” or “Gastric fluid”
`
`
`
`
`
`
`
`“Dissolving…and either erosion of said matrix or diffusion” g
`
`(PO’s construction)
`
`“Releases substantially all of said drug after immersion (’280)” or “Releases
`substantially all of said drug within about ten hours after immersion (’475)”
`
`“remains substantially intact until all of said drug is released”
`“Extending the release rate…while releasing substantially all”
`
`Source: IPR2014-00379, Resp. 27-30; Reply 2-4
`.
`
`37
`
`

`
`
`The “substantially intact” limitation does The “substantially intact” limitation does
`
`not exclude formulations that erodenot exclude formulations that erode
`
`The method claims of the ’475 patent allow for release by erosion and also
`require that the dosage form remains substantially intact.
`
`’803 Patent
`
`Source: IPR2014-00379, Exh. 1001, ’475 patent, claim 43; Reply 2-3
`.
`38
`
`

`
`
`The ’803 patent explicitly discloses a dosage form The ’803 patent explicitly discloses a dosage form
`
`that remains substantially intactthat remains substantially intact
`
`’803 Patent
`
`(Exh. 1005, 7:16-20)
`
`It also teaches that the dosage form is designed to remain in theIt also teaches that the dosage form is designed to remain in the
`stomach for the sustained retention period, i.e., the “time between the
`administration of single doses of an active agent time equal to or
`
`exceeding at least twice the duration that is intended to be g
`administered more than once over a 24 hour period” [e.g., at least 16
`hours for drugs administered three times a day]. (Exh. 1005, 9:21-29)
`
`Source: IPR2014-00379, Reply 2-3
`.
`
`39
`
`

`
`
`
`The ’803 patent: “swells…to promote retention” limitationThe ’803 patent: “swells…to promote retention” limitation
`
`Polymer swelling promotes gastric retention according to the ‘803 patent:
`
`’803 Patent
`
`(Exh. 1005, 12:42-44)
`
`’803 patent teaches optimal dimensions in the swollen state to promote gastric retention:
`
`
`
`(Id 28:65 29:3)(Id., 28:65-29:3)
`
`(Id., 15:29-32)
`
`Sourc

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