`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Adckess: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexanckia, Virgit~ia 22313-1450
`www.uspto.gov
`
`I APPLICATION NO.
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`10/514,352
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`l
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`FILING DATE
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`11/12/2004
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`FIRST NAMED INVENTOR
`
`] ATTORNEY DOCKET NO. I CONFIRMATION NO.]
`
`Hans WimPieterVermeersch
`
`TIP-0033 US
`
`9009
`
`11/03/2008
`
`27777
`7590
`PHILIP S. JOHNSON
`JOHNSON & JOHNSON
`ONE JOHNSON & JOHNSON PLAZA
`NEW BRUNSWICK, NJ 08933-7003
`
`I
`I
`
`I
`
`EXAMINER ]
`
`CHANG, CELIA C
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`ART UNIT
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`l
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`PAPER NUMBER
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`]
`
`1625
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`11/03/2008
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`PAPER
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`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`The time period for reply, if any, is set in the attached communication.
`
`PTOL-90A (Rev. 04/07)
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`Lupin Ex. 1050 (Page 1 of 9)
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`
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`Office Action Summary
`
`Application No.
`
`Applicant(s)
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`10/514,352
`
`Examiner
`
`VERMEERSCH ET AL.
`
`Art Unit
`
`Celia Chang
`1625
`-- The MAILING DATE of this communication appears on the cover sheet with the correspondence address --
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE 3 MONTH(S) OR THIRTY (30) DAYS,
`WHICHEVER IS LONGER, FROM THE MAILING DATE OF THIS COMMUNICATION.
`Extensions of time may be available under the provisions of 37 CFR 1.136(a). In no event, however, may a reply be timely filed
`after SIX (6) MONTHS from the mailing date of this communication.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication.
`Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
`earned patent term adjustment. See 37 CFR 1.704(b).
`
`Status
`1)[]
`2a)[~
`3)[--I
`
`Responsive to communication(s) filed on 14 July 2008.
`This action is FINAL. 2b)[--I This action is non-final.
`Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
`closed in accordance with the practice under Ex parte Quayle, 1935 C.D. 11,453 O.G. 213.
`
`Disposition of Claims
`
`4)[~ Claim(s) 19-32 is/are pending in the application.
`
`4a) Of the above claim(s) __ is/are withdrawn from consideration.
`Claim(s) 23 is/are allowed.
`Claim(s) 19,20,22 and 24-32 is/are rejected.
`Claim(s) 21 is/are objected to.
`Claim(s) __ are subject to restriction and/or election requirement.
`
`5)[]
`6)[~
`7)[~
`8)[]
`
`Application Papers
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`9)[--I The specification is objected to by the Examiner.
`10)[--I The drawing(s) filed on __ is/are: a)[--I accepted or b)[--I objected to by the Examiner.
`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121(d).
`11)1--1 The oath or declaration is objected to by the Examiner. Note the attached Office Action or form PTO-152.
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`Priority under 35 U.S.C. § 119
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`12)[--I Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`
`a)[--I All b)[--I Some * c)[--I None of:
`1.[--I Certified copies of the priority documents have been received.
`2.[--I Certified copies of the priority documents have been received in Application No. __
`3.[--I Copies of the certified copies of the priority documents have been received in this National Stage
`application from the International Bureau (PCT Rule 17.2(a)).
`¯ See the attached detailed Office action for a list of the certified copies not received.
`
`Attachment(s)
`
`1 ) [] Notice of References Cited (PTO-892)
`2) [] Notice of Draftsperson’s Patent Drawing Review (PTO-948)
`
`3) [] Information Disclosure Statement(s) (PTO/SB/08)
`Paper No(s)/Mail Date 7/14/08.
`
`4) [] Interview Summary (PTO-413)
`Paper No(s)/Mail Date.__
`5) [] Notice of Informal Patent Application
`
`6) [] Other:__
`
`U.S. Patent and Trademark Office
`PTOL-326 (Rev. 08-06)
`
`Office Action Summary
`
`Part of Paper No./Mail Date 20081023
`
`Lupin Ex. 1050 (Page 2 of 9)
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`
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`Application!Control Number: 10/514,352
`Art Unit: 1625
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`Page 2
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`DETAILED ACTION
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`1.
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`Amendment and response filed by applicants dated July 14, 2008 have been entered and
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`considered carefully.
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`Claims 1-18 have been canceled. New claims 19-32 have been presented.
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`2.
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`The rejection of claims 1-11 and 17 under 35 USC 112 second paragraph is also
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`applicable to the new claims 19-20, 22, 24-28.
`
`Please note that the new claim 19 is drawn to ethanolate solvate of (3R,3aS,6aR)-
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`hexahydrofuro [2,3-b] furan-3-yl ( 1 S,2R)-3- [ [(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-
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`benzyl-2- hydroxypropylcarbamate ; claim 20 is drawn to the compound to ethanol ratio ranges
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`between 5:1 and 1:5; claim 22 is a solvate additionally comprising water. This is very
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`confusing as to what is the product being claimed. Please note that each solvate is an
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`independent chemical material with specific chemnical identity (see Seddon previously recited).
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`Is it a single solvate? Multiple solvate? Or a three component ethanol-water-(3R,3aS,6aR)-
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`hexahydrofuro [2,3-b] furan-3-yl ( 1 S,2R)-3- [ [(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-
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`benzyl-2- hydroxypropylcarbamate? Please note monosolvate, di-solvate, mono-ethanol
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`monohydrate etc. are all different chemical identities which have different elemental content,
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`chemical properties and physical properties. In addition, the "comprising" scope of claim 22
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`allows inclusion of other components, thus, indefinite numbers of products. The scope of claims
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`19-20, 22, 26-28 cannot be ascertained.
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`It is unclear what is the process of claims 24-25 since the term "inducing" lacks steps and
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`does not provide the necessary particularity of how the process is being carried out.
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`3.
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`The rejection of claim 12 under 35 USC 112 first paragraph, as failing to comply with
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`the enablement requirement is now applicable to newly added claims 24-25. The claims contain
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`subject matter which was not described in the specification in such a way as to enable one skilled
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`in the art to which it pertains, or with which it is most nearly connected, to make and/or use the
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`invention.
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`"The standard for determining whether the specification meets the enablement
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`requirement [in accordance with the statute] was cast in the Supreme Court decision of Mineral
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`Lupin Ex. 1050 (Page 3 of 9)
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`
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`Application!Control Number: 10/514,352
`Art Unit: 1625
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`Page 3
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`Separation v. Hyde, 242 U.S. 261,270 (1916) which postured the question: is the
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`experimentation needed to practice the invention undue or unreasonable? That standard is still
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`the one to be applied. In re Wands’, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
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`Accordingly, even though the statute does not use the term "undue experimentation," it has been
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`interpreted to require that the claimed invention be enabled so that any person skilled in the art
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`can make and use the invention without undue experimentation. In re Wands’, 858 F.2d at 737, 8
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`USPQ2d at 1404 (Fed. Cir. 1988). See also United States v. Telectronics, Inc., 857 F.2d 778,
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`785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988) ("The test of enablement is whether one reasonably
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`skilled in the art could make or use the invention from the disclosures in the patent coupled with
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`information known in the art without undue experimentation.").
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`In the instant case, the claim is drawn to a process of making any crystalline material
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`with any molecular composition by contacting the compound (3R,3aS,6aR)-hexahydrofuro [2,3-
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`b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2-
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`hydroxypropylcarbamate, form A which is a product having (3R,3aS,6aR)-hexahydrofuro [2,3-b]
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`furan-3-yl ( 1 S,2R)-3- [ [(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2-
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`hydroxypropylcarbamat with an organic solvent. Based on the level of skill as stated in the state
`
`of the art reference Kirk-Othmer Encyclopedia of Chemical Technology Copyright © 2002 by
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`John Wiley & Sons, Inc., pp. 95-147, Article Online Posting Date: August 16, 2002, the amount
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`of guidance in the specification, the disclosure does not contain sufficient information to enable
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`one skilled in the pertinent art for recovery of such a product as claimed.
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`Specifically, the amount of guidance or direction needed to enable an invention is
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`inversely related to the amount of knowledge in the state of the art as well as the predictability in
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`the art. In reFisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970). The "amount of
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`guidance or direction" refers to that information in the application, as originally filed, that
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`teaches exactly how to make or use the invention. The more that is known in the prior art about
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`the nature of the invention, how to make, and how to use the invention, and the more predictable
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`the art is, the less information needs to be explicitly stated in the specification. In contrast, if
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`little is known in the prior art about the nature of the invention and the art is unpredictable, the
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`specification would need more detail as to how to make and use the invention in order to be
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`enabling. In the field of chemistry generally, there may be times when the well-known
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`Lupin Ex. 1050 (Page 4 of 9)
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`
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`Application!Control Number: 10/514,352
`Art Unit: 1625
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`Page 4
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`unpredictability of chemical reactions will alone be enough to create a reasonable doubt as to the
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`accuracy of a particular broad statement put forward as enabling support for a claim. This will
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`especially be the case where the statement is, on its face, contrary to generally accepted scientific
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`principles. Most often, additional factors, such as the teachings in pertinent references, will be
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`available to substantiate any doubts that the asserted scope of objective enablement is in fact
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`commensurate with the scope of protection sought and to support any demands based thereon for
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`proof."
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`In the instant case, the state of the art ofpolymorph recovery is highly unpredictable. See
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`for example Kirk-Othmer Encyclopedia of Chemical Technology Copyright © 2002 by John
`
`Wiley & Sons, Inc., pp. 95-147, Article Online Posting Date: August 16, 2002. This article
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`indicates that many uncertain factors determine morphology, and specifically that the appearance
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`of the crystalline product and its processing characteristics (such as washing and filtration) are
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`affected by crystal habit (i.e., the general shape of a crystal). Relative growth rates of the faces of
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`a crystal determine its shape. Faster growing faces become smaller than slower growing faces
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`and, in the extreme case, may disappear from the crystal altogether. Growth rates depend on the
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`presence of impurities, rates of cooling, temperature, solvent, mixing, and supersaturation.
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`Furthermore, the importance of each of these factors may vary from one crystal face to another,
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`see page 114.
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`The reference also teaches that polymorphism is a condition wherein crystalline form is
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`intimately associated with processing ("Polymorphism is a condition in which chemically
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`identical substances may crystallize into different forms. Each form is, however, only stable
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`(thermodynamically) in a certain range of temperature and pressure. In the case of ambient
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`pressure, eg, ammonium nitrate exhibits four changes in form between - 18 and 125°C:
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`",, ~9,:~:~ C-
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`",, ~,:~. ~ C~
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`8-t:~~" ~)
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`~ ~3° ~)
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`- 5~ ~’C
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`Transitions from one polymo~hic fo~ to another may be accompanied by changes in
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`process conditions (temperature, pressure, shear or solution composition), transitions ~om one
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`polymo~hic fo~ to another and lead to fo~ation of a solid product with unacceptable
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`properties (eg, melting point or dissolution rate).
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`Lupin Ex. 1050 (Page 5 of 9)
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`
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`Application!Control Number: 10/514,352
`Art Unit: 1625
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`Page 5
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`In general, as stated by Braga (p.3640 right column provided previously), it is well
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`recognized that "...if the formation of polymorphs is a nuisance for crystal engineers, solvate
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`formation can be a nightmare, because it is extremely difficult to predict whether a new species
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`may crystallizes from solution with one or more molecules of solvent".
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`It is even more confusing that the crystals may "comprising" water. If solvents and water
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`are impurities, one having ordinary skill in the art is well aware of the mechanism by which
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`impurities can be incorporated into crystalline products: adsorption of impurities on crystal
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`surfaces, solvent entrapment in cracks, crevices and agglomerates and inclusion of pockets of
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`liquids etc.. A key factor in solving problems associated with crystal purity is identification of
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`the mechanism of impurity in cooperation. (see Kirk-Othmer p. 116-117 provided previously).
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`Inclusion of impurity is not a new product, not a new solvate, and not a new crystal. Therefore,
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`such well recognized state-of-the-art teaching clearly support that upon obtaining a crystal of
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`(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl]
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`(isobutyl) amino]-l-benzyl-2- hydroxypropylcarbamate:ethanol in 1:1 ratio, absent of factual
`
`evidence, no extrapolation can be predicted to (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1
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`S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropyl
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`carbamate:ethanol in 1:5 to 5:1, indefinite number or possible distinct compounds.
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`Isolation of a specific crystal having an identifiable chemical identity is strictly empirical.
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`The isolation of (3R,3 aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3- [ [(4-aminophenyl)
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`sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropylcarbamate:ethanol in 1:1 ratio, does not
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`offer any support for (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-
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`aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropylcarbamate:ethanol, even in
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`1: "x" ratio or any other solvents such as water with the compound. One must obtain the
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`product upon employing a process with very specific and empirical conditions with no
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`predictability to any other product or process. The term "inducing" lacks how such process can
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`be operated.
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`4.
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`The rejection of claims 1-11, 16-17 are rejected under 35 U.S.C. 112, first paragraph, as
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`failing to comply with the enablement requirement now applicable to claims 19-20, 22 and 28-32
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`is maintained. The claims contain subject matter which was not described in the specification in
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`Lupin Ex. 1050 (Page 6 of 9)
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`
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`Application!Control Number: 10/514,352
`Art Unit: 1625
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`Page 6
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`such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly
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`connected, to make and/or use the invention.
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`The rational of high degree of unpredictablility in processes of making unknown solvates
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`as delineated supra is also applicable here and incorporated by reference. Absent of operable
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`process for making the claimed products together with the well recognized state-of-the-art
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`teaching by Braga (p.3640 right column) that it is well recognized in the art "...if the formation
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`ofpolymorphs is a nuisance for crystal engineers, solvate formation can be a nightmare, because
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`it is extremely difficult to predict whether a new species may crystallizes from solution with one
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`or more molecules of solvent", that is, every species of crystalline solvate is an empirical
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`enablement on its own and no predictability can be made on products which were not factually
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`supported; in the instant case, ethanolate of5:1 to 1:5 other than the 1:1 compound, ethanolate
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`also containing indefinite amount of salvation water. Since the active material was not enabled,
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`neither can a composition containing such active material be enabled.
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`5.
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`Claims 26-27, 29-32 are rejected under 35 U.S.C. 112, first paragraph, as failing to
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`comply with the written description requirement. The claims contain subject matter which was
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`not described in the specification in such a way as to reasonably convey to one skilled in the
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`relevant art that the inventors, at the time the application was filed, had possession of the claimed
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`invention.
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`On page 21 of the specification, general process of preparing pharmaceutical composition
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`was disclosed using liquid carrier or liquid processing carrier. It is well recognized in the art that
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`solvate would be dissoluted upon contacting with liquids/solvents. Nowhere in the specification
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`provided support that what excipient would maintain a pharmaceutical composition comprising a
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`(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl]
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`(isobutyl) amino]-l-benzyl-2- hydroxypropyl carbamate:ethanol 1:1 with all the crystalline
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`properties. A solid composition comprising compound of claim 23 was not presented.
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`6.
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`The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the
`
`basis for the rejections under this section made in this Office action:
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`Lupin Ex. 1050 (Page 7 of 9)
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`
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`Application!Control Number: 10/514,352
`Art Unit: 1625
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`Page 7
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`A person shall be entitled to a patent unless (b) the invention was patented or described in a printed publication in
`this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application
`for patent in the United States.
`
`The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all
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`obviousness rejections set forth in this Office action:
`
`(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in
`section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are
`such that the subject matter as a whole would have been obvious at the time the invention was made to a person
`having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the
`manner in which the invention was made.
`
`Claims 26-27 are rejected under 35 U.S.C. 102(b) as being anticipated by, or
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`alternatively, claims 26-27 are rejected under 35 U.S.C. 103(a) as being unpatentable over WO
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`99/67417.
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`WO 99/67417 disclosed the compound (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1
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`S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropylcarbamate (see
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`figure 5A) which was tested after preparation into a stock solution i.e. pharmaceutical
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`composition (see p. 11 and p.75). To the extend that the claims are drawn to "compositions" of
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`pseudomorph of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl)
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`sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropylcarbamate, which upon contacting such
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`crystal with liquid would form the same identical composition as the stock preparation of WO
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`99/67417, anticipation was found.
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`To the extend that the claims are drawn to (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-
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`yl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropyl
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`carbamate:ethanol in 1:1 ratio in a pharmaceutical composition, such composition is prima facie
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`obvious over WO 99/67417. Please note that, it was clearly stated in the specification (see p.21)
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`that the instant pharmaceutical compositions of the solvates are made with liquids such as
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`aqueous, alcohol, oil etc. Upon contacting a solvate with a liquid solvent, the crystal would be
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`dissolved, thus, a solution of solvents containing (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl
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`(1 S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropylcarbamate
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`would be obtained. Such solution would be identical with the disclosure of WO 99/67417 p.75,
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`or an obvious variation (employing alternative carriers) as taught by pages 52-57 of the article.
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`Lupin Ex. 1050 (Page 8 of 9)
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`Application!Control Number: 10/514,352
`Art Unit: 1625
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`Page 8
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`There is nothing unobvious in preparing additional conventional composition of a known product
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`by picking and choosing an alternative carrier as guided by the prior art (p.52-57).
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`7.
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`Claim 23 is allowed.
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`Claim 21 is objected to as being dependent upon a rejected base claim, but would be
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`allowable if rewritten in independent form including all of the limitations of the base claim and
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`any intervening claims.
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`8.
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`Applicants’ amendment necessitated the new grounds of rejections.
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`THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as
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`set forth in 37 CFR 1.136(a).
`
`A shortened statutory period for reply to this final action is set to expire THREE
`MONTHS from the mailing date of this action. In the event a first reply is filed within TWO
`MONTHS of the mailing date of this final action and the advisory action is not mailed until after
`the end of the THREE-MONTH shortened statutory period, then the shortened statutory period
`will expire on the date the advisory action is mailed, and any extension fee pursuant to 37
`CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event,
`however, will the statutory period for reply expire later than SIX MONTHS from the mailing
`date of this final action.
`
`9. Any inquiry concerning this communication or earlier communications from the
`examiner should be directed to Celia Chang, Ph. D. whose telephone number is 571-272-0679.
`The examiner can normally be reached on Monday through Thursday from 8:30 am to 5:00 pm.
`
`If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
`supervisor, Janet L. Andres, Ph. D., can be reached on 571-272-0867. The fax phone number for
`the organization where this application or proceeding is assigned is 571-273-8300.
`
`Information regarding the status of an application may be obtained from the Patent
`Application Information Retrieval (PAIR) system. Status information for published applications
`may be obtained from either Private PAIR or Public PAIR. Status information for unpublished
`applications is available through Private PAIR only. For more information about the PAIR
`system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR
`system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
`
`OA CS/Chang
`Oct. 22, 2008
`
`/Celia Chang/
`Primary Examiner
`Art Unit 1625
`
`Lupin Ex. 1050 (Page 9 of 9)