UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Adckess: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virgit~ia 22313-1450
`www.uspto.gov
`
`I APPLICATION NO.
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`12/536,807
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`FILING DATE
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`08/06/2009
`
`FIRST NAMED INVENTOR
`
`] ATTORNEY DOCKET NO. I CONFIRMATION NO.]
`
`Hans Wim Pieter VERMEERSCH
`
`TIP-0033USDIV1
`
`4088
`
`EXAMINER ]
`
`CHANG, CELIA C
`
`ART UNIT
`
`1
`
`PAPER NUMBER
`
`1625
`
`]
`
`]
`
`09/12/2011
`
`27777
`7590
`PHILIP S. JOHNSON
`JOHNSON & JOHNSON
`ONE JOHNSON & JOHNSON PLAZA
`NEW BRUNSWICK, NJ 08933-7003
`
`I
`I
`
`I NOTIFICATION DATE
`
`[
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`DELIVERY MODE
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`09/12/2011
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`ELECTRONIC
`
`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.
`
`Notice of the Office communication was sent electronically on above-indicated
`following e-mail address(es):
`
`"Notification Date" to the
`
`j njuspatent @ corus.j nj.com
`lhowd @its.jnj.com
`gsanche@its.jnj.com
`
`PTOL-90A (Rev. 04/07)
`
`Lupin Ex. 1009 (Page 1 of 9)
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`

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`Office Action Summary
`
`Application No.
`
`Applicant(s)
`
`12/536,807
`
`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 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)[--I Responsive to communication(s) filed on 12 October 2020.
`
`2a)[--I This action is FINAL. 2b)[~ This action is non-final.
`3)1--1 An election was made by the applicant in response to a restriction requirement set forth during the interview on
`; the restriction requirement and election have been incorporated into this action.
`4)1--1 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 Exparte Quayle, 1935 C.D. 11,453 O.G. 213.
`
`Disposition of Claims
`
`5)[~ Claim(s) 15-22 is/are pending in the application.
`
`5a) Of the above claim(s) __ is/are withdrawn from consideration.
`Claim(s) __ is/are allowed.
`Claim(s) 15-22 is/are rejected.
`Claim(s) __ is/are objected to.
`Claim(s) __ are subject to restriction and/or election requirement.
`
`6)[--I
`7)[~;~
`8)1--1
`9)[--I
`
`Application Papers
`
`10)[--I The specification is objected to by the Examiner.
`11 )[--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).
`12)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
`
`13)[--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 8/6/09, 10/16/09.
`
`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. 03-11 )
`
`Office Action Summary
`
`Part of Paper No./Mail Date 20110830
`
`Lupin Ex. 1009 (Page 2 of 9)
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`

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`Application/Control Number: 12/536,807
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`Art Unit: 1625
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`DETAILED ACTION
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`1.
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`This application is a divisional of SN 10/514,352.
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`Claims 1-14 have been canceled.
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`Claims 15-22 are pending.
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`Page 2
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`2.
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`Claims 15-22 are rejected under 35 U.S.C. 112, second paragraph, as being indefinite for
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`failing to particularly point out and distinctly claim the subject matter which applicant regards as
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`the invention.
`
`It is unclear whether the product of claim 15 is the same as that of claim 16; or the
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`composition of claim 17 is the same as that of claim 18 or the relationship among claims 19-22
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`and their base claims.
`
`Please note that a crystalline form can exist as a solvate of a hydrate, thus, it is unclear
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`what is claim 16 or 18 etc. because it is unclear whether a "solvate" of formula in claim 16 is
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`"the" hydrate of the formula or a solvate of the formula. The same rational also applies to claims
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`17, 19-22.
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`If they are the same product, then, it is recommended that the term "solvate" be deleted
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`from claims 17 and 18 to be consistent of the claiming of ~_ product.
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`3.
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`Claims 19 and 21 are rejected to under 35 U. S. C. 112 4~ paragraph or 37 CFR 1.75(c),
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`as being of improper dependent form or for failing to further limit the subject matter of a
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`previous claim. Please note that claims 19 and 21 depends on a composition for which no
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`antecedent basis was found in the base claim. It is further questioned that since the composition
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`comprises other than the compounds of the base claim, whether the claims are further limiting of
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`the base scope. Applicant is required to cancel the claims, or amend the claims to place the
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`claims in proper dependent form.
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`The following is a quotation of the first paragraph of 35 U.S.C. 112:
`
`The specification shall contain a written description of the invention, and of the manner and process of making
`and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it
`
`Lupin Ex. 1009 (Page 3 of 9)
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`

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`Application/Control Number: 12/536,807
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`Page 3
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`Art Unit: 1625
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`pertains, or with which it is most nea~:ly connected, to make and use the same and shall set forth the best mode
`contemplated by the inventor of carrying out his invention.
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`Claims 15-22 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with
`
`the written description requirement. The claims contain subject matter which was not described
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`in the specification in such a way as to reasonably convey to one skilled in the relevant art that
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`the inventors, at the time the application was filed, had possession of the claimed invention.
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`A survey of the specification as compare with the prior art has been made and the
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`analysis is as following:
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`It is well known in the art that a compound per se and a salt, solvate or hydrate of the
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`compound are not the same chemical product i.e. different chemical identity (Seddon). There is
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`no predictability in possession of a compound per se to be in possession of any solvate, hydrate
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`or mixed solvateihydrate (see Braga, cited on 1449). Since it is considered that in possession of
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`the compound per se to predict any form of solvate/hydrate is a nightmare, one can only patent
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`the product after showing possession of such a product.
`
`The specification, on p.23, disclosed that, form B has the characteristic as:
`
`"Form B: a weight loss of 3.4% was observed in the temperature range 25-78°C (water)
`and of 5.1% in the temperature range 25-110°C (ethanol + water for T>78°C). From
`110-200°C further 1.1% weight was lost (ethanol)."
`
`There is insufficient antecedent basis to support the scope of claim 15 wherein the hydrate is a
`
`monohydrate i.e. 1:1 ratio. There is no description for the claims being hydrate of the compound
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`(3 R,3 aS,6aR)- hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl) sulfonyl]
`
`(isobutyl) amino]-l-benzyl-2- hydroxypropyl carbamaterin which the ratio of compound to water
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`is about 1:1 because the characteristic of form B as indicated supra included loss of water and
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`ethanol; also because there was no explicit process of how to make the 1:1 ratio hydrate (see
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`process p.22-23 only described steps for form D). Were the 1:1 ratio hydrate made by the same
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`steps as disclosed on p.22-23, example 2, there is no information as to how water or ethanol were
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`included. Were the 1:1 ratio hydrate made by alternative processes, the claims would constitute
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`claiming a new matter. Nowhere in the specification such a product was prepared or the
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`structural formula of claim 16 or 18 be found.
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`Lupin Ex. 1009 (Page 4 of 9)
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`

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`Application/Control Number: 12/536,807
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`Art Unit: 1625
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`Page 4
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`5.
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`The following is a quotation of the first paragraph of 35 U.S.C. 112:
`
`The specification shall contain a written description of the invention, and of the manner and process of making
`and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the axt to which it
`pertains, or with which it is most neaxly connected, to make and use the same and shall set forth the best mode
`contemplated by the inventor of carrying out his invention.
`
`Claims 15-22 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
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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 requirement
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`was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261,270
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`(1916), where the Supreme Court looked to whether the experimentation needed to practice an
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`invention was undue or unreasonable. Id. An invention must be described so that any person
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`skilled in the art can make and use the invention without undue experimentation. In re Wands,
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`858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). As stated in the MPEP 2164.01(a) "There
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`are many factors to be considered when determining whether there is sufficient evidence to
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`support a determination that a disclosure does not satisfy the enablement requirement and
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`whether any necessary experimentation is "undue". The analysis must consider all the evidence
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`related to each of these factors, and any conclusion of nonenablement must be based on the
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`evidence as a whole. Id. at 740, Id. at 1407. The factors to be considered herein are those set
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`forth as the In re Wands, 8 USPQ 2nd 1400 (1988) decision.
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`The analysis is applied to the instant case.
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`Nature ol" invention
`
`The claims are drawn to polymorphic crystalline forms of (3 R,3aS,6aR)- hexahydrofuro
`[2,3-bl furan-3-yl (1 S,2R)-3-[[(4-arninophenyl)sulfonyl] (isobutyl) arninol-l-benzyl-2-
`hydroxypropyl carbamaterin. Polymorphic forms are highly specific chemical compounds with
`particular molecular packing. A hydrate or solvate of the same compound is not a polymorphic
`form but a different chemical entity (see Seddon)
`
`Breadth ol" the claims
`
`The claims are drawn to hydrate of (3 R,3aS,6aR)- hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-
`[[(4-aminophenyl)sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropyl carbamaterin, wherein
`the compound to water is 1:1. To claim such a product, the monohydrate of the compound
`must be prepared.
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`Lupin Ex. 1009 (Page 5 of 9)
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`

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`Application/Control Number: 12/536,807
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`Art Unit: 1625
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`Page 5
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`The state of the art and predictability
`The standard of the amount of guidance or direction needed to enable an invention is
`inversely related to the amount of knowledge in the state of the art as well as the predictability in
`the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of
`guidance or direction" refers to that information in the application, as originally filed, that
`teaches exactly how to make or use the invention. The more that is known in the prior art about
`the nature of the invention, how to make, and how to use the invention, and the more predictable
`the art is, the less information needs to be explicitly stated in the specification. In contrast, if
`little is known in the prior art about the nature of the invention and the art is unpredictable, the
`specification would need more detail as to how to make and use the invention in order to be
`enabling. In the field of chemistry generally, there may be times when the well-known
`unpredictability of chemical reactions will alone be enough to create a reasonable doubt as to the
`accuracy of a particular broad statement put forward as enabling support for a claim. This will
`especially be the case where the statement is, on its face, contrary to generally accepted scientific
`principles. Most often, additional factors, such as the teachings in pertinent references, will be
`available to substantiate any doubts that the asserted scope of objective enablement is in fact
`commensurate with the scope of protection sought and to support any demands based thereon for
`proof."
`In the instant case, specific crystal preparation requires very limited and specific process
`to obtain consistent single crystalline forms. Based on the level of skill as stated in the state of
`the art reference Kirk-Othmer Encyclopedia of Chemical Technology Copyright © 2002 by John
`Wiley & Sons, Inc., pp. 95-147, Article Online Posting Date: August 16, 2002, the amount of
`guidance in the specification, the disclosure does not contain sufficient information to enable one
`skilled in the pertinent art for recovery of such a product as claimed.
`The Kirk-Othmer reference (cited on 1449) evidenced that the state of the art of
`polymorph recovery is highly unpredictable (See for example pp. 95-147). The article indicates
`that many uncertain factors determine morphology, and specifically that the appearance of the
`crystalline product and its processing characteristics (such as washing and filtration) are affected
`by crystal habit (i.e., the general shape of a crystal). Relative growth rates of the faces of a
`crystal determine its shape. Faster growing faces become smaller than slower growing faces and,
`in the extreme case, may disappear from the crystal altogether. Growth rates depend on the
`presence of impurities, rates of cooling, temperature, solvent, mixing, and supersaturation.
`Furthermore, the importance of each of these factors may vary from one crystal face to another,
`see page 114.
`The reference also teaches that polymorphism is a condition wherein crystalline form is
`intimately associated with processing ("Polymorphism is a condition in which chemically
`identical substances may crystallize into different forms. Each form is, however, only stable
`(thermodynamically) in a certain range of temperature and pressure. In the case of ambient
`pressure, eg, ammonium nitrate exhibits four changes in form between -18 and 125°C:
`
`Transitions from one polymorphic form to another may be accompanied by changes in
`process conditions (temperature, pressure, shear or solution composition), transitions from one
`polymorphic form to another and lead to formation of a solid product with unacceptable
`properties (eg, melting point or dissolution rate).
`
`Lupin Ex. 1009 (Page 6 of 9)
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`

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`Application/Control Number: 12/536,807
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`Art Unit: 1625
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`Page 6
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`Isolation of a specific polymorph in absence of other forms may be absolutely essential
`for a crystalline product, eg., one polymorph may have a more desirable color or greater hardness
`or disperse in water more easily than another polymorph etc.
`
`Level of ordinary skill
`It is evidenced in the art (Gysephem) that for the particular compound (3 R,3aS,6aR)-
`hexa- hydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl] (isobutyl) amino]d-
`benzyl-2- hydroxypropyl carbamaterin, its ethanol solvate and hydrate will interconvert with
`each other under laboratory conditions and the characteristic of the solvent loss disclosed on p.23
`being:
`
`"Form B: a weight loss of 3.4% was observed in the temperature range 25-78°C (water)
`and of 5.1% in the temperature range 25-110°C (ethanol + water for T>78°C). From
`l lO-200°Cfurther 1.1% weight was lost (ethanol)."
`is consistent with such observation in the art. That is, the product described on p.23 is a mixed
`solvateihydrate and no ration of 1:1 was evidenced.
`One having ordinary skill in the art is well aware of that there is no predictability in
`possession of a compound per se to be in possession of any solvate, hydrate or mixed
`solvateihydrate, see Braga et al. p.3640:
`"One can say that if the formation of polymorphs is a nueisance for crystal engineersm
`solvate formation can be a nightmare ..... "
`
`Amount of experimentation/guidance
`The process of obtaining reproducible and stable polymorphic forms are very specific and
`small changes in the processing will result in different product (see Kirk-Othmer supra). It is
`also well recognized that polymorphic forms are critical for its property and bioavailability, the
`possession of the exact chemical composition with its physical properties must be identified for
`the product and claims drawn to such identifiable product can be made.
`It is disclosed on p.22-23, example 2, that:
`
`"In another example a mixture of Form D and Form B were prepared. Acetone was used
`as a solvent during the crystallisation process to form Form D. The crystallisation
`process then comprised the step of stirring the initial starting compound (lOg) in 70ml
`acetone. The solution was subsequently refluxed until the compound was completely
`solved. 40 ml of water were added and the solution was subsequently cooled slowly until
`room temperature and stirred overnight. Formed crystals were filtered and dried in the
`vacuum oven at 50°C. 7.6 g &product resulted from the crystallization, being the yield of
`this process of about 75%. "
`
`It is unclear how form B was made whether the same process or different process or how
`different was form B made from using acetone for form D.
`
`In view of the state of the field that prediction of solvateihydrate would be a nightmare, it
`is concluded that in possession of a product which included (3 R,3aS,6aR)- hexa- hydrofuro
`[2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl] (isobutyl) amino]-l-benzyl-2-
`hydroxypropyl carbamaterin water and ethanol would need undue experimentation to obtain a
`
`Lupin Ex. 1009 (Page 7 of 9)
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`

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`Application/Control Number: 12/536,807
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`Art Unit: 1625
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`Page 7
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`compound which is a hydrate of (3 R,3 aS,6aR)- hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-
`[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-l-benzyl-2- hydroxypropyl carbamaterin which
`the ratio of compound to water is about 1:1.
`
`Working examples
`Example 2 disclosed:
`
`"In another example a mixture of Form D and Form B were prepared. Acetone was used
`as a solvent during the crystallisation process to form Form D. The crystallisation
`process then comprised the step of stirring the initial starting compound (lOg) in 70ml
`acetone. The solution was subsequently refluxed until the compound was completely
`solved. 40 ml of water were added and the solution was subsequently cooled slowly until
`room temperature and stirred overnight. Formed crystals were filtered and dried in the
`vacuum oven at 50°C. 7.6 g &product resulted from the crystallization, being the yield of
`this process of about 75%. "
`
`Example 4 disclosed:
`
`"Form B: a weight loss of 3.4% was observed in the temperature range 25-78°C (water)
`and of 5.1% in the temperature range 25-110°C (ethanol + water for T>78°C). From
`110-200°Cfurther 1.1% weight was lost (ethanol)."
`
`The above examples provided observation that based on the disclosure of p.23, there is
`insufficient enabling support for the claims being hydrate of the compound (3 R,3aS,6aR)-
`hexahydrofuro [2,3-b] furan-3-yl (1 S,2R)-3-[[(4-aminophenyl)sulfonyl] (isobutyl) amino]-l-
`benzyl-2- hydroxypropyl carbamaterin which the ratio of compound to water is about 1:1
`because the characteristic of form B as indicated included loss of water and ethanol; also because
`there was no explicit process of how to make the 1:1 ratio hydrate. Were the 1:1 ratio hydrate
`made by the same stepd as disclosed on p.22-23, there is no information as to how water or
`ethanol were included. Were the 1:1 ratio hydrate made by alternative processes, the claims
`would constitute claiming a new matter.
`
`5.
`
`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 pro.
`
`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
`
`Lupin Ex. 1009 (Page 8 of 9)
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`

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`Application/Control Number: 12/536,807
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`Art Unit: 1625
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`Page 8
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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
`
`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
`Sept. 1, 2011
`
`/Celia Chang/
`Primary Examiner
`Art Unit 1625
`
`Lupin Ex. 1009 (Page 9 of 9)