UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`LUYE PHARMA GROUP LTD., LUYE PHARMA (USA) LTD.,
`SHANDONG LUYE PHARMACEUTICAL CO., LTD., and NANJING LUYE
`PHARMACEUTICAL CO., LTD.,
`Petitioners,
`v.
`ALKERMES PHARMA IRELAND LTD and ALKERMES CONTROLLED
`THERAPEUTICS, INC.,
`Patent Owners.
`________________
`
`Case IPR2016-01096
`U.S. Patent No. 6,667,061
`________________
`
`PATENT OWNERS’ DEMONSTRATIVES
`ORAL HEARING – AUGUST 28, 2017
`
`

`

`’061 Patent
`Exh. 1001
`
`Col. 4, ll. 57-62.
`
`Decision (Paper 13) at 3; Patent Owners’ Response, 5-6, 8, 32, 39, 41; Exh. 2014 at
`¶¶ 84, 156.
`
`2
`
`

`

`Petitioners’ Expert’s Testimony
`
`“ . . . A particle in water’s going to settle
`pretty fast. In honey, it’s going to take a
`long time. But it would be difficult to inject
`the honey over water.”
`
`DeLuca 1st Dep. Tr.
`Exh. 2016 at
`97:10-13
`
`Petitioners' Reply (Paper 40) at 5-6, Exh. 1024 at ¶ 21.
`
`3
`
`

`

`‘TEST EXAMPLE 1
`
`Kino
`Kino
`Exh. 1010
`Exh. 1010
`
`TEST EXAMPLE 3
`
`A 25 mg portion of each of the bromperidol-containing
`microsphere preparations obtained from the following For-
`mulations A and B was dispersed in 20 ml of physiological
`saline and shaken at 37° C, and at 80 revolutions per minute
`using a constant temperature shaker (manufactured by
`Yamato Kagaku), Thereafter, samples were periodically
`collected to calculate drug releasing ratio by ultraviolet
`absorption photometry (245 nm), As shownin FIG,3, it was
`confirmed that the microsphere preparation of Formulation
`A which comprises finely ground bromperidol can release
`the drug at a rate of almost 0 order.
`
`Each of the bromperidol-containing microsphere prepa-
`rations obtained in Examples 1 to 3 was suspended in
`physiological saline and administered into the femoral
`United S muscle of male SD rats (15 weeks of agc) in a dosc of 12.5
`. sp microspheres whichremained intheadministeredareawere
`scan,
`14g a8 bromperidol, After a predetermined period of time,
`iit eet. periodically recovered to measure remaining amount of
`0) dao, bromperidol. Asthe result, release of the drug at an almost
`0 at constant tate was confirmed as shown in FIG.1.
`Rebar
`ay comuneTen K. Pago:
`Tibitircoet SPeccedneresltlienisal Flesraral
`[63] Coertnreatice-in-port of POTTPSOAMATI, Nev. 15, 100,
`ee Agent, om Fire—Supheus, Mion, Fina, Maspeak
`a)
`Porcge Applicattun Priseity Lista
`Now, 07, 0002
`QF] Bagereen $0 7
`(i) Tat.c.*
`seman
`ome AGL S50
`Bn
`ee
`(2) Us. C1 .
`AAD, eee Atcian mretedphere petperntion, which. is Lai
`by aia breeesayehotte drug
`(SE) Pied OP Search cectcscscssmsssssssn4H40
`_
`2447, 459. 529, 550; soa *compely etch
`I
`1.4. PATENT DOCLRMENTS
`Kelerimces Cited
`wreak)jecid or the like, and a process for the production
`JATAALS LISTE Boswell ot tl. oocccsmmmemen: SIS
`@ Claims, 4 Driveing Shects
`
`19:17-24.
`
`(56)
`
`eal
`a
`
`@ EXAMPLE|
`,fvempic =
`
`TEST EXAMPLE4
`
`A 15 mg portion of cach of the haloperidol-containing
`microsphere preparations obtained from the following For-
`mulations C and D was dispersed in 20 ml of physiological
`Saline and shaken at 37° C. and at 80 revolutions per minute
`using a constant
`temperature shaker (manufactured by
`Taitech), and samples were periodically collected to calcu-
`late drug releasing ratio by ultraviolet absorption photom-
`etry (245 nm). As shown in the FIG.4, it was confirmedthat
`the microsphere preparation of Formulation C which com-
`prises finely ground haloperidol can release the drug at a rate
`of almost 0 order.
`
`Patent Owners' Response (Paper 33) at 11; Exh. 2014 at ¶¶ 83-84; Exh. 2081 at
`Patent Owners’ Response (Paper 33) at 11; Exh. 2014 at | 83-84; Exh. 2081 at
`19:17-24.
`
`4
`
`

`

`’061 Patent
`Exh. 1001
`
`1. A composition suitable for injection through a
`needle into a host, comprising:
`microparticles comprising a polymeric binder; and
`an injection vehicle, wherein said microparticles are
`suspended in said injection vehicle
`at a concentration of greater than about 30 mg/ml
`to form a suspension,
`wherein a fluid phase of said suspension has a
`viscosity greater than about 20 cp and less than
`about 600 cp at 20°C.,
`wherein the viscosity of said fluid phase of said
`suspension provides injectability of the composition
`through a needle ranging in diameter from 18-22.
`
`Decision (Paper 13) at 4; Patent Owners' Response (Paper 33) at 5.
`
`5
`
`

`

`Inherency
`
`“Inherency, however, may not be established by
`probabilities or possibilities. The mere fact that
`a certain thing may result from a given set of
`circumstances is not sufficient.”
`
`Continental Can Co. U.S.A. v. Monsanto Co., 948
`F.2d 1264, 1269 (Fed. Cir. 1991) (emphasis
`added)
`
`Patent Owners' Response (Paper 33) at 17, 38.
`
`6
`
`

`

`Inherency
`“A party must, therefore, meet a high standard in order to
`rely on inherency to establish the existence of a claim
`limitation in the prior art in an obviousness analysis—the
`limitation at issue necessarily must be present, or the
`natural result of the combination of elements explicitly
`disclosed by the prior art.”
`
`Par Pharm., Inc. v. TWi Pharms., Inc., 773 F.3d 1186,
`1195-96 (Fed. Cir. 2014) (emphasis added).
`
`Patent Owners' Response (Paper 33) at 16; Patent Owners' Preliminary Response
`(Paper 11) at 13.
`
`7
`
`

`

`Inherency
`
` Millennium Pharms. Inc. v. Sandoz Inc., 862 F.3d 1356,
`1367 (Fed. Cir. 2017).
`
` Honeywell Int'l Inc. v. Mexichem Amanco Holding S.A.
`DE C.V., No. 2016-1996, 2017 WL 3254943, at *2 (Fed.
`Cir. Aug. 1, 2017).
`
`8
`
`

`

`Petitioners’ Reliance on Johnson and Gustafsson
`
`Johnson Injection
`Vehicle
`“The injection vehicle was
`an aqueous vehicle
`containing 3% w/v
`Carboxymethyl Cellulose
`(sodium salt), 1% v/v
`Tween 20 (Polysorbate 20)
`and 0.9% sodium chloride.”
`
`Gustafsson Injection
`Vehicle
`“The vehicle for injection
`was physiological sodium
`chloride solution containing
`3% of sodium
`carboxymethylcellulose as
`suspension aid.”
`
`Exh. 1009 at 12:42-45
`
`Exh. 1011 at 18:19-24
`
`Decision (Paper 13) at 11, 21; Petition (Paper 5) at 33, 50.
`
`9
`
`

`

`Unmet Inherency Burden
`
`
`
`
`
`Petitioners’ Argument:
`CMC at 3% always necessarily has a viscosity within the
`•
`claimed range of the patent, regardless of any other
`ingredients or how they are mixed.
`
`Petitioners’ Attempt:
`Ignores the numerous types and grades of CMC;
`•
`Ignores how the injection vehicle is made;
`•
`Ignores other ingredients in injection vehicles;
`•
`Improperly relies on Mark Tracy Declaration (not prior
`•
`art); and
`Relies on unsupported opinion of expert, Dr. DeLuca.
`
`•
`
`Patent Owners' Response (Paper 33) at 9, 19, 20; Patent Owners' Preliminary
`Response (Paper 11) at 13.
`
`10
`
`

`

`Aqualon Brochure
`Exh. 2034 at 6
`
`Patent Owners’ Response (Paper 33) at 22-24, 26-27; Petitioners’ Reply (Paper 40) at
`19; Exh. 1024 at 18-19, 26, 38.
`
`11
`
`

`

`Handbook of
`Pharm. Excipients
`Exh. 1008 at 78-79
`
`Patent Owners’ Response (Paper 33) at 22-24.
`
`12
`
`

`

`Ashland Ref. Guide
`Exh. 2038 at 40
`
`Patent Owners’ Response (Paper 33) at 23.
`
`13
`
`

`

`CMC Spec.
`Sheets
`Exhs. 2036, 2038,
`2039
`
`Patent Owners’ Response (Paper 33) at 23.
`
`14
`
`

`

`Viscosity Grades of CMC
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at 122:3-
`7, 123:24-124:5
`
`Q. So a person of skill in the art could use a
`medium viscosity grade CMC as an injection
`vehicle for a microparticle?
`
`A. It could.
`
`Q. Okay. But in your opinion it’s possible for a
`high viscosity grade CMC to be used as an
`injection vehicle for a microparticle, right?
`
`A. It’s possible.
`
`Patent Owners’ Obs. (Paper 50) at 1.
`
`15
`
`

`

`Factors Affecting Viscosity
`
`• CMC Viscosity Grade
`
`• Other ingredients, e.g., polysorbate and NaCl
`
`• How injection vehicle is made and/or sterilized
`
`• Order of addition of ingredients, e.g., NaCl
`
`The ’061 patent claims a viscosity range, not a
`specific formulation.
`
`Patent Owners' Response (Paper 33) at 21, 25, 27-28.
`
`16
`
`

`

`Johnson Disclosure
`• No disclosure of CMC Grade
`
`• 10 times more polysorbate than in an
`embodiment in ’061 patent
`
`• No disclosure of how injection vehicle is made
`and/or sterilized
`
`• No disclosure of order of addition of sodium
`chloride
`
`The ’061 patent claims a viscosity range, not a
`specific formulation.
`
`Patent Owners' Response (Paper 33) at 21, 25, 27-28.
`
`17
`
`

`

`Polysorbate Could Affect Viscosity
`
`Q. So the addition of polysorbate in the aqueous
`solution with CMC can impact CMC directly or
`indirectly, right, through these interactions?
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`236:20-25
`
`A. It could.
`
`Patent Owners' Obs. (Paper 50) at 5-6.
`
`18
`
`

`

`Sodium Chloride Affects Viscosity
`
`“But as Dr. Berkland pointed out,
`whether the solute is added before
`or after the CMC affects the
`viscosity obtained . . . .”
`
`“. . . add[ing] CMC after sodium
`chloride, thereby lead[s] to lower
`viscosities.”
`
`DeLuca Supp.
`Decl.
`Exh. 1024 ¶ 68
`
`Patent Owners' Obs. (Paper 50) at 4-5.
`
`19
`
`

`

`Aqualon Brochure
`Exh. 2034 at 12
`
`Patent Owners' Response (Paper 33) at 27.
`
`20
`
`

`

`| Solute added after CMCNS—feaSR_
`~NSCbeforeCMC
`
`Patent Owners' Response (Paper 33) at 32.
`
`
`
`
`T
`0.2
`
`T
`
`Tl
`
`0.4
`
`0.8 1.0
`
`Molal concentration of cation (including counterion)
`
`Figure 9. Effect of solutes on viscosity of sodium carboxymethyl
`cellulose (CMC) (Aqualon® sodium carboxymethylcellulose).
`NaCl (circle and triangle); NaCl + NaOH (pH 10.1) (circle with cross
`through); Na,SO, (circle); Na,P,0,.10H,0 (pH 9.5-9.8) (square);
`KCI or LiCI (cross).
`
`Patent Owners' Response (Paper 33) at 32.
`
`21
`
`Guo 1998
`Guo 1998
`Exh. 2043 at 260
`Exh. 2043 at 260
`
`— — —
`
`gf A
`Solute added
`
`!
`
`co oO
`
`60-4
`
`—,
`Ww)
`oO
`
`&==u
`
`w
`oOoO
`2>
`>|
`Cc
`o=
`oO
`oO
`
`o<
`
`reviews
`
`|
`
`research focus
`
`Pharmaceuti:
`naturally occ
`polymers
`Jian-Hwa Guo, G.W. Ski
`
`Pobyriees: susct as tyedennypirogyleet
`carboxymethyl cellulose, beytemcyp
`pyrrolidone, pectin, carragecnan seve
`in the pharmaceutical
`industry, ae
`charecberization are perfonmed with
`solution; this 8 becuase the ther
`solutinns can be readily measured ar
`of the size and structure of
`the
`characterization ofthe pelymer. The
`Properties: and practical apgicntines
`
` T
`
`10
`0.02
`
`0.04
`
`TT
`0.08 0.1
`
`

`

`Gustafsson
`Exh. 1011 at
`18:16-24
`
`Petition (Paper 5) at 11, 39, 40, 43, 49-52; Patent Owners' Response (Paper 33) at
`36, 54, 56.
`
`22
`
`

`

`Injectable Suspensions Should Be Sterile
`
`Q. You also mentioned sterility, that the injection
`suspension has to be sterile; is that right?
`
`A. Yes.
`
`DeLuca 1st Dep. Tr.
`Exh. 2016 at 89:3-
`8.
`
`Q. Ok. And it has to be sterile because you’re
`injecting it into the body, I suspect.
`
`A. Yes.
`
`Patent Owners' Response (Paper 33) at 26; Exh. 2014 at ¶ 64.
`
`23
`
`

`

`Handbook of
`Pharmaceutical
`Excipients
`Exh. 1008 at 80
`
`Patent Owners' Response (Paper 33) at 26; Exh. 2014 at ¶ 65.
`
`24
`
`

`

`’061 Patent
`Exh. 1001 at 11:28-32
`
`Patent Owners' Response (Paper 33) at 27; Exh. 2014 at ¶ 65.
`
`25
`
`

`

`Mixing Affects Viscosity
`
`Berkland Decl.
`Exh. 2014 at ¶ 67-
`69, see also ¶ 130
`
`“CMC can form both physical and chemical
`interactions with itself which increase
`viscosity.”
`
`“More polymer chain entanglement occurs
`with increasing CMC concentration, which in
`turn increases the viscosity of the overall
`solution due to large increases in the
`resistance to flow. (See Exh. 2031, DeLuca
`1996 at 291.)”
`
`“Additionally, CMC can exhibit inter- and intra-
`molecular interactions that affect viscosity,
`such as hydrogen bonding or electrostatic
`bonding . . . . The more of these interactions,
`the more viscous the solution becomes.”
`
`Patent Owners' Response (Paper 33) at 24, 26-27.
`
`26
`
`

`

`Mixing Affects Viscosity
`
`Q. . . . Dr. DeLuca, you understand that Dr. Berkland
`also testified in his last declaration that the method of
`dissolution or mixing could impact viscosity. Do you recall
`that?
`
`A. Yes.
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`238:21-239:12
`
`Q. For instance, using different mixing methods and
`speeds could result in solutions having different
`viscosities. Do you recall that?
`
`A. Yes.
`
`Q. Now you didn't dispute that in your reply declaration,
`correct?
`
`A. That's correct.
`
`Patent Owners' Obs. (Paper 50) at 6.
`
`27
`
`

`

`Polymer Chain Entanglement
`
`DeLuca 1st Dep. Tr.
`Exh. 2016 at
`182:10-19; 184:4-6
`
`Q. My question is: What is polymer chain entanglement?
`
`A. Just that there's, you know, an entanglement of the
`polymer chains. They're not linked. They're not linear.
`They're pretty much kind of mixed together and tangled,
`and, I guess, it's like if you get your hair all tangled up in
`a whirlpool. It may resemble that.
`
`Q. Okay.
`
`A. But it's -- the chains are kind of mixed in with each
`other.
`
`Q. So other additives may impact the entanglement as
`well?
`
`A. Yes.
`
`Patent Owners' Response (Paper 33) at 27-28.
`
`28
`
`

`

`Vehicles of ’061 Patent, Johnson, or Gustafsson
`
`Johnson
`(12:42-45)
`
`Gustafsson
`(18:19-24)
`
`’061 Patent
`(Claim 1,
`9:46)
`Accounted for
`in claimed
`viscosity
`Accounted for
`in claimed
`viscosity
`
`Factor
`
`CMC Viscosity
`Grade
`
`Order of
`Addition of
`Ingredients
`(e.g., NaCl)
`Method of
`Mixing
`
`Sterilization
`
`Accounted for
`in claimed
`viscosity
`Accounted for
`in claimed
`viscosity
`Decision (Paper 13) at 10, 23; Petition (Paper 5) at 11, 39, 40, 43, 49-52; Patent
`Owners' Response (Paper 33) at 21, 22, 25, 27-28, 36, 38, 54, 56.
`
`29
`
`

`

`Inherency
`
`“Inherency, however, may not be established by
`probabilities or possibilities. The mere fact that
`a certain thing may result from a given set of
`circumstances is not sufficient.”
`
`Continental Can Co. U.S.A. v. Monsanto Co., 948
`F.2d 1264, 1269 (Fed. Cir. 1991) (emphasis
`added)
`
`Patent Owners' Response (Paper 33) at 16-17, 38.
`
`30
`
`

`

`Patent Owners’ Testing – Exh. 2059
`
`•
`
`Johnson and Gustafsson injection vehicles were
`created and tested. (See Table 1.)
`• Viscosity of the Johnson and Gustafsson
`injection vehicles fell outside the claimed range.
`(See Table 2.)
`• Dr. Gehrke disclosed the exact method and
`ingredients he used for his testing. (¶¶ 6-11)
`• Dr. Gehrke disclosed his raw data. (App. 2)
`• Petitioners chose not to depose Dr. Gehrke.
`
`Patent Owners' Response (Paper 33) at 18, 23, 37; Exh. 2014 at ¶¶ 47-50, 121-24.
`
`31
`
`

`

`Patent Owners’ Testing
`
`Gehrke Decl.
`Exh. 2059 at
`Table 1
`
`Patent Owners' Response (Paper 33) at 18, 23, 37; Exh. 2014 at ¶¶ 47-50, 121-24.
`
`32
`
`

`

`Patent Owners’ Testing
`
`Gehrke Decl.
`Exh. 2059 at
`Table 2
`
`Patent Owners' Response (Paper 33) at 18, 23, 37; Exh. 2014 at ¶¶ 47-50, 121-24.
`
`33
`
`

`

`Patent Owners’ Testing
`
`Gehrke Decl.
`Exh. 2059 at
`Table 2
`
`Patent Owners' Response (Paper
`33) at 18, 23, 37; Exh. 2014 at ¶¶
`47-50, 121-24.
`
`34
`
`

`

`Aqualon
`Brochure
`Exh. 2034 at 3-4
`
`• Pharmaceuticals
`
`• Cosmetics (e.g., toothpaste, lotions)
`
`• Food (e.g., protein foods, beverages)
`
`• Adhesives (e.g., wallpaper paste)
`
`• Coatings (e.g., latex paints)
`
`• Among others…
`
`Patent Owners' Obs. (Paper 50) at 3-4; Exh. 1024 at ¶ 42.
`
`35
`
`

`

`’657 Patent
`Exh. 2076
`
`“The carboxymethylcellulose Blanose 7ULC®
`(degree of substitution equal to 0.7) is
`dissolved in distilled water.”
`Col. 11, ll. 51-52
`
`“The compositions according to the invention
`and the suspensions obtained by redispersion
`of these compositions can be used in . . .
`formulations intended for the cosmetics
`and/or detergency or food sectors . . . .”
`Col. 10, ll. 53-58
`
`Patent Owners' Obs. (Paper 50) at 2; Exh. 2081 at 163:14-167:7.
`
`36
`
`

`

`Petitioners’ New Arguments
`
`Petition
`
`NO mention of commercial
`availability of CMCs
`NO mention of
`pharmaceutical grade
`CMCs
`NO mention of low
`viscosity CMCs (citing
`specifically to Johnson
`Example 7 which does not
`state “low”)
`
`Petitioners’ Reply
`(Paper 40)
`Commercial availability (p.
`8-9, 10, 14)
`Pharmaceutical grade (p.
`8, 10, 11, 13, 18)
`
`Low viscosity grade (p. 11,
`13, 16, 18) (citing
`Johnson’s other examples
`that state “low”)
`
`Petition (Paper 5) at 33-35; Petitioners' Reply (Paper 40) at 8-11, 13-14, 16, 18.
`
`37
`
`

`

`Petitioners’ New Arguments
`
`“[T]he Board must base its decision on arguments
`that were advanced by a party, and to which the
`opposing party was given a chance to
`respond.”
`
`In re Magnum Oil Tools Int'l, Ltd., 829 F.3d 1364,
`1381 (Fed. Cir. 2016) (internal citation omitted)
`
`Patent Owners' Response (Paper 33) at 47.
`
`38
`
`

`

`Petitioners’ New Arguments
`“We also note, as a final matter, that none of the
`points raised by [Petitioner’s expert] in his reply
`declaration (Exhibit 1041) were made in his
`initial declaration (Exhibit 1011) served with the
`Petition, or in the Petition itself.”
`
`Avaya Inc. et al. v. Network-1 Security Solutions,
`Inc., IPR2013-00071, Paper 103 at 28 (P.T.A.B.
`May 22, 2014)
`
`Patent Owners' Response (Paper 33) at 17.
`
`39
`
`

`

`Rules Prohibit New Arguments
`35 U.S.C. § 312(a)(3)
`
`Requirements of Petition.—A petition filed under
`section 311 may be considered only if—
`
`(3) the petition identifies, in writing and with
`particularity, each claim challenged, the grounds
`on which the challenge to each claim is based,
`and the evidence that supports the grounds for
`the challenge to each claim
`
`Patent Owners' Motion to Exclude (Paper 51) at 2-3, 11-14.
`
`40
`
`

`

`Dr. DeLuca’s Unsupported Circular Testimony
`
`“A particle in water’s going to
`settle pretty fast. In honey, it’s
`going to take a long time. But it
`would be difficult to inject the
`honey over water.”
`
`Petitioners’ Reply:
`“So something like water, with a
`negligible viscosity of 1cp, will
`allow particles to settle quickly,
`whereas particles suspending in
`honey, with a viscosity of about
`10,000cp, would take much
`longer to settle.”
`
`Dr. DeLuca’s Second
`Declaration:
`“So something like water, which
`has a relatively negligible
`viscosity of 1cp, will allow settling
`of the agent quickly. An agent
`placed in honey, with an
`approximate viscosity of about
`10,000cp … would take much
`longer to settle.”
`
`Petitioners' Reply (Paper 40) at 5-6, 15; Exh. 2016 at 97:7-11; Exh. 1024 at ¶¶ 16-
`17; Exh. 1024 at ¶ 21.
`
`41
`
`

`

`37 C.F.R. § 42.65(a)
`
`“Expert testimony that does not disclose the
`underlying facts or data on which the opinion
`is based is entitled to little or no weight.”
`
`Patent Owners' Response (Paper 33) at 19, 48.
`
`42
`
`

`

`Petitioners’ Expert’s Inherency Standard
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`150:14-151:10.
`
`Q. So your understanding of inherency is that CMC
`will fall within the range identified in the
`specification for viscosity plus or minus 10
`percent?
`
`A. . . . It's inherent that it's going to be -- it's
`going to be within a similar value, maybe not be
`the same but it certainly would be in a range that's
`-- that's, you know, could be within, you know, 10
`percent of the value.
`
`Patent Owners' Obs. (Paper 50) at 6-7.
`
`43
`
`

`

`Petitioners’ Expert’s Inherency Standard
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`151:20-152:13
`
`Q. . . . So what -- what is the inherent property of
`CMC that you are referring to when you were
`mentioning inherency in your reply report with
`respect to that compound?
`
`A. That if the low grade -- if a certain grade was
`being used, that a microparticle, which might be
`different, a different product, but similar in size
`and concentration, one would expect the viscosity
`to be in the range of that that's what we are
`referring to.
`
`Q. Right. And then you said within a margin of
`error, which is plus or minus 10 percent?
`
`A. Yeah. Yes.
`
`Patent Owners' Obs. (Paper 50) at 6-7.
`
`44
`
`

`

`Petitioners’ New Arguments
`
`• Commercial Availability
`
`• Pharmaceutical Grade
`
`• Low Viscosity Grade
`
`Petitioners' Reply (Paper 40) at 8-11, 13-15; Exh. 1024 at ¶¶ 31-36, 40-46, 50-52,
`56-60, and 86-89.
`
`45
`
`

`

`Petitioners’ New Arguments
`
`• Commercial Availability
`
`• Pharmaceutical Grade
`
`• Low Viscosity Grade
`
`Petitioners' Reply (Paper 40) at 8-11, 13-15; Exh. 1024 at ¶¶ 31-36, 40-46, 50-52,
`56-60, and 86-89.
`
`46
`
`

`

`’632 Patent
`Exh. 2074
`
`“Examples of suitable commercial products are
`Blanose 7M®, Blanose 7UL®, Blanose 7EL® and
`Ambergum 3021® from Aqualon.”
`Col. 2, ll. 15-17
`
`Patent Owners' Obs. (Paper 50) at 2; Exh. 2081 at 159:21-160:5.
`
`47
`
`

`

`’657 Patent
`Exh. 2076
`
`“The carboxymethylcellulose Blanose 7ULC®
`(degree of substitution equal to 0.7) is dissolved
`in distilled water.”
`Col. 11, ll. 51-52
`
`Patent Owners' Obs. (Paper 50) at 2; Exh. 2081 at 163:14-167:7.
`
`48
`
`

`

`Petitioners’ Expert Agrees re:
`Commercial Availability
`
`Q. But you would agree, at least, that Blanose
`7UL® and 7EL® were commercially available as of
`the time of the invention, right?
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`167:21-25
`
`A. Yes.
`
`Patent Owners' Obs. (Paper 50) at 2; Exh. 2081 at 167:21-25.
`
`49
`
`

`

`Petitioners’ New Arguments
`
`• Commercial Availability
`
`• Pharmaceutical Grade
`
`• Low Viscosity Grade
`
`Petitioners' Reply (Paper 40) at 8-11, 13-15; Exh. 1024 at ¶¶ 31-36, 40-46, 50-52,
`56-60, and 86-89.
`
`50
`
`

`

`Petitioners’ New Arguments
`
`• Commercial Availability
`
`• Pharmaceutical Grade
`
`• Low Viscosity Grade
`
`Petitioners' Reply (Paper 40) at 8-11, 13-15; Exh. 1024 at ¶¶ 31-36, 40-46, 50-52,
`56-60, and 86-89.
`
`51
`
`

`

`Petitioners’ Expert Uses Non-Pharmaceutical
`Grade CMC in His Research
`
`Q. My question is, you used food grade in [your]
`study, correct?
`
`A. Um-hmm. Looking at the date, 1995. Okay.
`Okay. This is -- this was done in 1995. All right.
`Okay.
`
`Q. So in your paper in looking for an appropriate
`vehicle for drug delivery you used CMC 7HF and
`7LF, correct?
`
`A. Yes.
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`134:12-135:3
`
`Patent Owners' Obs. (Paper 50) at 1-2.
`
`52
`
`

`

`Viscosity Does Not Change Between
`Pharmaceutical and Food Grade CMC
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`136:20-137:4
`
`Q. And so the viscosity doesn't change between
`food grade, pharma grade and industrial grade?
`
`A. No.
`
`Q. They do not change, correct?
`
`A. Right. The number 7 refers to the degree of
`substitution of the basic unit so.
`
`Patent Owners' Obs. (Paper 50) at 1.
`
`53
`
`

`

`Petitioners’ New Arguments
`
`• Commercial Availability
`
`• Pharmaceutical Grade
`
`• Low Viscosity Grade
`
`Petitioners' Reply (Paper 40) at 8-11, 13-15; Exh. 1024 at ¶¶ 31-36, 40-46, 50-52,
`56-60, and 86-89.
`
`54
`
`

`

`Petitioners’ New Arguments
`
`• Commercial Availability
`• Commercial Availability
`
`• Pharmaceutical Grade
`• Pharmaceutical Grade
`
`• Low Viscosity Grade
`• Low Viscosity Grade
`
`Petitioners' Reply (Paper 40) at 8-11, 13-15; Exh. 1024 at ¶¶ 31-36, 40-46, 50-52,
`56-60, and 86-89.
`
`55
`
`

`

`7UL and 7EL are Low Viscosity Grade
`
`Patent Owners' Response (Paper 33) at 23.
`
`Exh. 2038 at 40
`56
`
`

`

`7UL and 7EL are Identified and Classified as “Low
`Viscosity Grade”
`
`Q. Well, you would agree with me that Aqualon
`Blanose 7ULC® is identified here [in Exh. 2076] as
`a low viscosity CMC, right?
`
`A. Yes.
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`166:21-25; 208:11-
`14
`
`Q. So here Ashland has classified its CMC 7UL®
`and 7EL® as low viscosity grade CMC, correct?
`
`A. Yes.
`
`Patent Owners' Obs. (Paper 50) at 2, 3.
`
`57
`
`

`

`’657 Patent
`Exh. 2076
`
`In the examples which follow, the following products
`are used:
`[]
`•
`• carboxymethylcellulose with a degree of
`substitution equal to 0.7; of low viscosity—
`product Aqualon (Blanose 7ULC);
`
`Col. 15, ll. 38-48.
`
`Patent Owners' Obs. (Paper 50) at 2-3; Exh. 2081 at 165:15-166:6.
`
`58
`
`

`

`Petitioners’ New Arguments
`
`• Commercial Availability
`
`• Pharmaceutical Grade
`
`• Low Viscosity Grade
`
`Petitioners' Reply (Paper 40) at 8-11, 13-15; Exh. 1024 at ¶¶ 31-36, 40-46, 50-52,
`56-60, and 86-89.
`
`59
`
`

`

`Patent Owners’ Testing
`
`Gehrke Decl.
`Exh. 2059 at
`Table 1
`
`Patent Owners' Response (Paper 33) at 18, 23, 37; Exh. 2014 at ¶¶ 47-50, 121-24.
`
`60
`
`

`

`Patent Owners’ Testing
`
`Gehrke Decl.
`Exh. 2059 at
`Table 2
`
`Patent Owners' Response (Paper 33) at 18, 23, 37; Exh. 2014 at ¶¶ 47-50, 121-24.
`
`61
`
`

`

`Petitioners’ New Arguments
`
`• Commercial Availability
`
`• Pharmaceutical Grade
`
`• Low Viscosity Grade
`
`Petitioners' Reply (Paper 40) at 8-11, 13-15; Exh. 1024 at ¶¶ 31-36, 40-46, 50-52,
`56-60, and 86-89.
`
`62
`
`

`

`Reliance on Tracy Declaration is Misplaced
`
`• Submitted for a different purpose and does not
`discuss inherency
`• Does not discuss viscosity across all CMC types
`• Discusses different prior art (Kino)
`• Discusses different injection vehicles (Kino)
`• Petitioners quote out of context
`
`Patent Owners' Preliminary Response (Paper 11) at 7-8, 20-22; Patent Owners'
`Response (Paper 33) at 20.
`
`63
`
`

`

`Office Action
`Exh. 1016 at 4
`
`“Therefore, absent unexpected results regarding
`the criticality of the viscosity, Kino disclosed all
`the limitations of the instant claims.”
`
`Patent Owners' Response (Paper 33) at 10.
`
`64
`
`

`

`Tracy Decl.
`Exh. 1018 at ¶ 3
`
`I have read and understood U.S. Patent
`3.
`No. 5,656,299 to Kino et al. (“the Kino patent”).
`The Kino patent does not explicitly disclose the
`viscosity of the injection vehicles used in the
`Test Examples. The Kino patent does not
`provide any information about injectability, or
`the relationship between injectability and
`viscosity of the injection vehicle.
`
`Patent Owners' Response (Paper 33) at 10, 60.
`
`65
`
`

`

`Tracy Decl.
`Exh. 1018 at ¶ 4
`
`Test Examples 1, 3, and 4 of the Kino
`4.
`patent use physiological saline as the injection
`vehicle. Based upon my knowledge and
`experience, the viscosity of the physiological
`saline injection vehicle as the fluid phase of a
`suspension containing the microspheres of each
`of Test Examples 1, 3, and 4 of the Kino patent
`is approximately one (1) centipose (cp) at
`20ºC.
`
`Patent Owners' Response (Paper 33) at 11.
`
`66
`
`

`

`Notice of
`Allowability
`Exh. 1019 at 2
`
`“The Declaration under 37 CFR 1.132 filed
`5/14/03 is sufficient to overcome the rejection
`of claims 1-21, 41-42 based upon 35 U.S.C.
`103(a).”
`
`Patent Owners' Preliminary Response (Paper 11) at 9; Patent Owners' Response (Paper
`33) at 13.
`
`67
`
`

`

`Tracy Decl.
`Exh. 1018
`
`Patent Owners' Preliminary Response (Paper 11) at 8, 21-22; Patent Owners'
`Response (Paper 33) at 11.
`
`68
`
`

`

`Petitioners’ Expert Testimony
`
`Q. Is it possible [Johnson Example 7 is] a
`different viscosity?
`
`A. Anything's possible. Yeah.
`
`DeLuca 1st Dep. Tr.
`Exh. 2016 at
`231:20-21; see also
`id. at 109:1-5;
`119:4-11.
`
`Patent Owners' Response (Paper 33) at 21, 23.
`
`69
`
`

`

`Reason to Combine
`
`“[A] party seeking to invalidate a patent as obvious
`must demonstrate by clear and convincing
`evidence that a skilled artisan would have had
`reason to combine the teaching of the prior art
`references to achieve the claimed invention, and
`that the skilled artisan would have had a
`reasonable expectation of success from doing
`so.'"
`In re Cyclobenzaprine Hydrochloride Extended-
`Release Capsule Patent Litig., 676 F.3d 1063, 1068-
`69 (Fed. Cir. 2012)
`
`Patent Owners' Response (Paper 33) at 60.
`
`70
`
`

`

`Reason to Combine
`
`“[T]here must be some articulated reasoning
`with some rational underpinning to support the
`legal conclusion of obviousness.”
`
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418
`(2007)
`
`Decision (Paper 13) at 19, 27; Patent Owners' Response (Paper 33) at 46-48.
`
`71
`
`

`

`’061 Patent
`Exh.1001
`
`Decision (Paper 13) at 15-17; Patent Owners’ Response (Paper 33) at 30-34.
`
`72
`
`

`

`Petitioners’ Asserted Motivation
`
`Petition (Paper 5) at 27.
`
`73
`
`

`

`Petitioners’ Asserted Motivation
`
`Petitioners’ Reply (Paper 40) at 17.
`
`74
`
`

`

`Ramstack
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`40:24-41:20.
`
`Q. So is it your opinion that a person of skill in the
`art would not consider density of the injection
`vehicle when developing an injectable
`formulation?
`
`A. Of?
`
`Q. Of a microparticle.
`
`A. It’s not necessary to really worry about it.
`
`Patent Owners’ Obs. (Paper 50) at 9-10.
`
`75
`
`

`

`’061 Patent
`Exh. 1001
`
`Decision (Paper 13) at 17-19; Patent Owners’ Response (Paper 33) at 44-48.
`
`76
`
`

`

`Petitioners’ Asserted Combinations
`
`Petition (Paper 5) at 46-47; Petitioners’ Reply (Paper 40) at 26.
`
`77
`
`

`

`“Could” Is Not Enough
`
`DeLuca Supp.
`Decl.
`Exh. 1024 at
`¶ 112
`
`Patent Owners’ Motion to Exclude (Paper 51) at 6; Exh. 1024 at ¶ 112.
`
`78
`
`

`

`“Could” is Not Enough
`
`“But that reasoning seems to say no more than that
`a skilled artisan, once presented with the two
`references, would have understood that they could
`be combined. And that is not enough: it does not
`imply a motivation to pick out those two references
`and combine them to arrive at the claimed
`invention.”
`
`Pers. Web Techs., LLC v. Apple, Inc., 848 F.3d 987,
`994 (Fed. Cir. 2017)
`
`Patent Owners’ Response (Paper 33) at 46.
`
`79
`
`

`

`Ramstack
`Exh. 1005 at 35-37
`
`Patent Owners’ Response (Paper 33) at 51, 53.
`
`80
`
`

`

`Ramstack
`Exh. 1005
`
`“In vivo studies in dogs were conducted on product
`provided as dry microparticles (Prodex 2, Prodex 3)
`and in lyophilized form (Prodex 4A, Prodex 4B, Prodex
`4C).”
`
`Exh. 1005 at 38, ll. 4-6.
`
`“Mean or median plasma concentrations and/or
`pharmacokinetic parameters of risperidone, 9-hydroxy-
`risperidone, and the active moiety for formulations
`Prodex 2/3/4A/4B/4C, are given in Table 1.”
`
`Exh. 1005 at 39, ll. 4-6.
`
`Patent Owners’ Response (Paper 33) at 51.
`
`81
`
`

`

`Ramstack
`Exh. 1005
`
`Patent Owners’ Response (Paper 33) at 54, 57.
`
`82
`
`

`

`Ramstack
`Exh. 1005 at 42
`
`Patent Owners’ Response (Paper 33) at 51.
`
`83
`
`

`

`Ramstack Has No Problems
`
`Q. And you don’t identify any problems with
`Ramstack’s PLGA risperidone containing
`microparticles, correct?
`
`A. No.
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`218:16-219:20
`
`Q. No, you did not?
`
`A. No, I did not.
`
`Q. I can make it easier. Did you identify any
`problems with any injection vehicle in Ramstack
`in your declarations?
`
`A. I didn't have any problem.
`
`Patent Owners’ Obs. (Paper 50) at 8.
`
`84
`
`

`

`Ramstack
`Exh. 1005
`
`Patent Owners’ Response (Paper 33) at 51, 53.
`
`85
`
`

`

`Gustafsson
`Exh. 1011
`
`“Primarily, however, the invention presents a
`solution to the previously described problem with
`active substances sensitive to or instable in
`organic solvents.”
`Exh. 1011 at 6:35-7:2.
`
`“Briefly the invention is based on the idea on
`entrapping the active ingredient in microparticles
`without using any organic solvent . . .”
`Exh. 1011 at 7, ll. 3-5.
`
`Patent Owners’ Response (Paper 33) at 35, 40-42, 52.
`
`86
`
`

`

`A POSA Would Not Replace BSA With Risperidone
`
`Q. So it is your opinion that a person of skill in the art
`could replace the BSA active in Gustafsson's
`microparticles with Ramstack's risperidone?
`
`A. You know, I don't know why you would do that but.
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`211:23-212:5,
`212:13-21
`
`Q. So just to make sure I understand. Your opinion is
`that a POSA could replace the BSA with -- in
`Gustafsson with Ramstack's risperidone but you don't
`see any reason why they would do that --
`
`A. Yeah.
`
`Q. -- right?
`
`A. Right.
`
`Patent Owners’ Obs. (Paper 50) at 8.
`
`87
`
`

`

`No Benefit in Gustafsson’s Vehicle
`
`Q. And Gustafsson doesn't identify that its
`injection--injection vehicle improves on any
`other injection vehicle, does it?
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at
`228:15-19
`
`A. No.
`
`Patent Owners’ Obs. (Paper 50) at 9.
`
`88
`
`

`

`No Benefit in Gustafsson’s Vehicle
`
`DeLuca 2nd Dep. Tr.
`Exh. 2081 at 228:9-
`14, 229:18-22
`
`Q. And [Example 7 of Gustafsson] says it uses
`CMC as a suspension aid; is that right?
`
`A. That's correct.
`
`Q. And it's well-known that CMC is a suspension
`aid, right?
`
`A. Yes, it is.
`
`Q. So there [in Ramstack] that was the injection
`vehicle that uses CMC. So the CMC [in]
`Ramstack is also used as a suspension aid,
`right?
`
`A. Yes.
`
`Patent Owners’ Obs. (Paper 50) at 8-9.
`
`89
`
`

`

`No Reason to Combine
`
`1. Ramstack did not disclose a problem with his
`risperidone microparticles or any part of the
`formulation.
`2. Gustafsson’s microparticles protect from organic
`solvents, which is irrelevant to risperidone.
`3. Dr. DeLuca confirmed a POSA would not have
`replaced the BSA active in Gustafsson’s
`microparticles with risperidone from Ramstack.
`4. CMC acts as a suspension aid in both Gustafsson
`and Ramstack.
`
`Patent Owners’ Response (Paper 33) at 44-57; Patent Owners’ Obs. (Paper 50) at
`8-9.
`
`90
`
`

`

`Conclusion
`• Johnson and Gustafsson lack sufficient
`information.
`
`• Petitioners do not and cannot prove inherency
`across all CMCs and injection vehicles.
`
`• Patent Owners' testing establishes no inherency.
`
`• Petitioners’ expert relies on wrong inherency
`standard.
`
`• Petitioners do not provide a motivation to
`combine in either ground.
`
`Patent Owners’ Response (Paper 33) at 1-62.
`
`91
`
`