UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Ofl]ce
`Ada~ss: COMMISSIONER FOR PATENTS
`P.O, Box 1450
`Alexandria, Virginia 22313-1450
`www.uspto.gov
`
`APPLICATION NO. ]
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`FILING DATE
`
`FIRST NAMED INVENTOR
`
`] ATTORNEY DOCKET NO.
`
`[ CONFIRNIATION NO.
`
`!
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`10/514,352
`
`11/12/2004
`
`Hans Wim Pieter Vermeersch
`
`TIP-0033 US
`
`9009
`
`27777 7590 01/14/2008
`PHILIP S. JOHNSON
`JOHNSON & JOHNSON
`ONE JOHNSON & JOHNSON PLAZA
`NEW BRUNSWICK, NJ 08933-7003
`
`EXAMINER
`
`CHANG, CELIA C
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`ART UNIT
`
`PAPER NUMBER
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`1625
`
`4/2008
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`PAPER
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`Please find below and/or attached an Office communication concerning this application or proceeding.
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`The time period for reply, if any, is set in the attached communication.
`
`PTOL-90A (Rev. 04/07)
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`Lupin Ex. 1048 (Page 1 of 10)
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`

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`Office Action Summary
`
`Application No.
`
`Applicant(s)
`
`10/514,352
`
`Examiner
`
`VERMEERSCH ET AL.
`
`Art Unit
`
`1625
`Celia Chang
`-- 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 pedod for reply is specified above, the maximum statutory pedod 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
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`1)1~ Responsive to communication(s) filed on 24 September 2007.
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`2a)l’-I This action is FINAL. 2b)[~ This action is non-final.
`3)1--I 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.
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`Disposition of Claims
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`4)1~ Claim(s) 1-13 and 15-17 is/are pending in the application.
`
`5)r3
`6)1~
`7)i--]
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`4a) Of the above claim(s) is/are withdrawn from consideration.
`is/are allowed.
`Claim(s) ¯
`Claim(s) 1-13, 15-17 is/are rejected.
`is/are objected to.
`Claim(s)
`Claim(s) __ are subject to restriction and/or election requirement.
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`Application Papers
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`9)[-I The specification is objected to by the Examiner.
`10)1--I The drawing(s) filed on ~ is/are: a)l--I accepted or b)l--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 .~21(d).
`11 )[--I 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)[-] Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
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`a)l--I All b)r-I Some * c)i--I None of:
`1 .I--1 Certified copies of the priority documents have been received.
`2.1---I Certified copies of the priority documents have been received in Application No. ~
`3.1--1 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)
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`1) [] Notice of References Cited (PTO-892)
`2) [] Notice of Draftsperson’s Patent Drawing Review (PTO-948)
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`3) [] Information Disclosure Statement(s) (PTO/SB/08)
`Paper No(s)/Mail Date __
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`4) [] Interview Summary (PTO-413)
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`Paper No(s)/Mail Date. ~
`5) [] Notice of Informal Patent Application
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`6) [] Other:__
`
`U.S. Patent and Trademark Office
`PTOL-326 (Rev. 08-06)
`
`Office Action Summary
`
`Part of Paper No./Mail Date 20080103
`
`Lupin Ex. 1048 (Page 2 of 10)
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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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`Applicant’s election of Group I, claims 9-10, with ethanolate as the elected species in the
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`reply filed on Sept. 24, 2007 is acknowledged. Because applicant did not distinctly and
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`specifically point out the supposed errors in the restriction requirement, the election has been
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`treated as an election without traverse (MPEP § 818.03(a)).
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`The requirement is still deemed proper and is therefore made FINAL.
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`Claim 14 has been canceled. Claims 15-17 have been added. Claims 1-13, 15-17 are
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`pending.
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`2.
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`Claims 1-11, 17 are rejected under 35 U.S.C. 112, second paragraph, as being indefinite
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`for failing to particularly point out and distinctly claim the subject matter which applicant
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`regards as the invention.
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`It is unclear what subject matter was being claimed. Please note that for utility patent, the
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`category of novel and unobvious product/material or compositions of matter can be claimed. It
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`is unclear what is a "pseudomorph". According to skilled person in the art (see Seddon) the
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`term "pseudomorph" is very ambiguous and does not define the chemical identity of a product.
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`The elected species which is (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-
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`arninophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropylcarbamate ethanolate 1:1, is
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`a single chemical product (see RN 635728-z~9-3). The chemical identity demarcates the elected
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`compound from the known compound (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-
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`3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropylcarbamate. Skilled
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`person in the chemical art does not call such a compound a pseudomorph. Seddon stated clearly
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`that such empirical use of the term should have been corrected with the modem advancement in
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`the art by clearly identify the products obtained using its chemical identify such as delineated by
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`CAS.
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`It is unclear what is the intended scope of the claims: Are they referring to the
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`compounds which have been obtained/possessed in the specification? Are they multiple
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`products which are extrapolated from the compounds obtained by the specification? Or are they
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`future products possibly obtained when solvents and (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-
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`Lupin Ex. 1048 (Page 3 of 10)
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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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`3-yl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2-
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`hydroxypropylcarbamate were brought together?
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`According to Seddon, solvates are chemically different products which should be named
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`according to its own chemical identity while forms are different packing solid material ~,ith
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`identical chemical and molecular composition thus it created enormous confusion when claims
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`are drawn to (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, form A which is a product
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`having (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, further, such from A
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`can "comprising water" in indefinite amount.
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`3.
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`Claim 12 is rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the
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`enablement requirement. The claims contain subject matter which was not described in the.
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`specification in such a way as to enable one skilled in the art to which it pertains, or with which
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`it is most nearly connected, to make and/or use the 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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`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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`Lupin Ex. 1048 (Page 4 of 10)
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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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`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
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`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 re Fisher, 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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`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
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`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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`Lupin Ex. 1048 (Page 5 of 10)
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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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`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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`169,6*
`liquid <
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`) tetr
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`Transitions from one polymorphic form to another may be accompanied by changes in
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`process conditions (temperature, pressure, shear or solution composition), transitions from one
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`polymorphic form to another and lead to formation of a solid product with unacceptable
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`properties (eg, melting point or dissolution rate).
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`In general, as stated by Braga (p.3640 right column), it is well recognized that "...if the
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`formation of polymorphs is a nuisance for crystal engineers, solvate formation can be a
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`nightmare, because it is extremely difficult to predict whether a new species may crystallizes
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`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
`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- l 17). Inclusion of impurity
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`is not a new product, not a new solvate, and not a new crystal. Therefore, such well recognized
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`state-of-the-art teaching clearly support that upon obtaining a crystal of (3R,3aS,6aR)-
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`Lupin Ex. 1048 (Page 6 of 10)
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`

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`Application/Control Number:
`10/514,352
`Art Unit: 1625
`
`Page 6
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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:ethanol in 1:1 ratio, absent of factual evidence, no
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`extrapolation can be predicted to (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:solvents in 1:5 or
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`5:1 or any other solvates.
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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,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: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 that may form solvates with the compound. One must obtain
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`the product upon employing a process with very specific and empirical conditions with no
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`predictability to any other product or process.
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`4.
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`Claims 1-11, 16-17 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply
`
`with the enablement requirement. The claims contain subject matter which was not described in
`
`the specification in such a way as to enable one skilled in the art to which it pertains, or with
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`which it is most nearly connected, to make and/or use the invention.
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`The rational of high degree ofunpredictablility inprocesses 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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`of polymorphs 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.
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`Lupin Ex. 1048 (Page 7 of 10)
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`

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`Application/Control Number:
`10/514,352
`Art Unit: 1625
`
`Page 7
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`5.
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`Claims 1-4, 6-13, 15-17 as interpreted by dependent claim 5 are rejected under 35
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`U.S.C. 112, second paragraph, as failing to set forth the subject matter which applicants regard as
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`their invention..Claim 5 fails to correspond in scope with which applicants have elected being
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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. It is very confusing
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`that how a "solvate" comprises a pharmaceutically acceptable composition? This claim rendered
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`other claims ambiguous whether the products are "compositions" containing compounds and
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`solvents or the claims are each individual compounds which are multiple component compounds
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`with (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 and ethanol, methanoll, acetaone, etc. in
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`specific ratio.
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`6.
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`Claims 13 and 15 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply
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`with the written description requirement. The claims contain subject matter which was not
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`described in the specification in such a way as to reasonably convey to one skilled in the relevant
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`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 the "solvates" in the solvated form or
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`crystal, that is, a pharmaceutical composition comprising a (3R,3aS,6aR)-hexahydrofuro [2,3-b]
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`furan-3-yl (1 $,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropyl
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`carbamate:ethanol in 1 : 1 ratio with all the crystalline properties.
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`7.
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`The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the
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`basis for the rejections under this section made in this Office action:
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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.
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`Lupin Ex. 1048 (Page 8 of 10)
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`

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`Application/Control Number:
`10/514,352
`Art Unit: 1625
`
`Page 8
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`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:
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`(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.
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`Claims 1-13, 15-17 are rejected under 35 U.S.C. 102(b) as being anticipated by, or
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`alternatively, claims 1-13, 15-17 are rejected under 35 U.S.C. 103(a) as being unpatentable over
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`WO 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] (i sobutyl) amino]-l-benzyl-2- hydroxyprop3;1
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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
`
`reference. There is nothing unobvious in preparing additional conventional composition of a
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`Lupin Ex. 1048 (Page 9 of 10)
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`

`
`Application/Control Number:
`10/514,352
`Art Unit: 1625
`
`Page 9
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`known product by picking and choosing an alternative carrier as guided by the prior art (p.52-
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`57).
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`8.
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`9.
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`No claim is allowed.
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`Any inquiry coiacerning this, communication or earlier communications from the
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`examiner should be directed to Celia Chang, Ph. D. whose telephone number is 571-272-0679.
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`The examiner can normally be reached on Monday through Thursday from 8:30 am to 5:00 pm.
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`If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
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`supervisor, Janet L. Andres, Ph. D., can be reached on 571-272-0867. The fax phone number
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`for the organization where this application or proceeding is assigned is 571-273-8300.
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`Information regarding the status of an appiication may be obtained from the Patent
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`Application Information Retrieval (PAIR) system. Status information for published applications
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`may be obtained from either Private PAIR or Public PAIR. Status information for unpublished
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`applications is available through Private PAIR only. For more information about the PAIR
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`system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR
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`system, contact the Electronic Business center (EBC) at 866-217-9197 (toll-free).
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`OACS/Chang
`Jan. 3, 2008
`
`Celia Chang
`Primary Examiner
`Art Unit 1625
`
`Lupin Ex. 1048 (Page 10 of 10)