UNITED STATES PATENT AND TRADEMARK OFFICE
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virgit~ia 22313-1450
`www.uspto.gov
`
`I APPLICATION NO.
`
`12/536,807
`
`l
`
`FILING DATE
`
`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
`
`]
`
`]
`
`45511
`7590
`05/22/2012
`WOODCOCK WASHBURN LLP
`CIRA CENTRE, 12TH FLOOR
`2929 ARCH STREET
`PHILADELPHIA, PA 19104-2891
`
`I
`I
`
`I NOTIFICATION DATE
`
`[
`
`DELIVERY MODE
`
`05/22/2012
`
`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 "Notification Date" to the
`following e-mail address(es):
`eofficemonitor @ woodcock.com
`
`PTOL-90A (Rev. 04/07)
`
`Lupin Ex. 1011 (Page 1 of 9)
`
`

`
`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)1~
`2a)[~;~]
`3)[--I
`
`4)I--1
`
`Responsive to communication(s) filed on 10 April 2012.
`This action is FINAL. 2b)[--I This action is non-final.
`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.
`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) 15-17,20,21 and23-36 is/are pending in the application.
`
`5a) Of the above claim(s) __ is/are withdrawn from consideration.
`Claim(s) __ is/are allowed.
`Claim(s) 15-17, 20-21, 23-36 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)[--I The oath or declaration is objected to by the Examiner. Note the attached Office Action or form PTO-152.
`
`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 11/9/11, 4/10/12.
`
`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 20120515A
`
`Lupin Ex. 1011 (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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`Page 2
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`DETAILED ACTION
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`1.
`
`Amendment and response filed by applicants dated Mar. 12, 2012 have been entered and
`
`considered carefully.
`
`Claims 1-14, 18-19, 22 have been canceled. Claims 23-36 have been added. Claims 15-
`
`17, 20-21, 23-36 are pending.
`
`2.
`
`The rejection of claims 15-22 (now 15-17, 20-21, 23-36) under 35 U.S.C. 112, second
`
`paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject
`
`matter which applicant regards as the invention.
`
`The current amendment in claim 15 drawn to "A hydrate" having ratio of the compound
`
`(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl ( 1 S,2R)-3- [ [(4-aminophenyl) sulfonyl]
`
`(isobutyl) amino]-l-benzyl-2- hydroxypropylcarbamate to water to be about 1:0.5 to 1:3 is
`
`confusing. Initially, it is unclear is there one hydrate, many hydrates or how many hydrates.
`
`Claims 16 makes claim 15 confusing because claim 16 is monohydrate yet claim 15 is a
`
`range and normally, the range is a continuous value. Claims 23-35 are unclear for the same
`
`reason that they are discrete compounds which chemically does not form a continuous range as
`
`its antecedent basis in the base claim 15.
`
`Since hydrates are known as hemihydrate, monohydrate, di-, tri-.., etc. if the claims are a
`
`group discrete compounds, the Markush elements are hemi-, mono, di- and tri-hydrate not a
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`range of water content.
`
`3.
`
`The rejection of claims 19 and 21 under 35 U. S. C. 112 4th paragraph or 37 CFR 1.75(c),
`
`as being of improper dependent form is dropped in view of cancelation of claim 19 and change
`
`of dependency of claim 21.
`
`4.
`
`The rejection of claims 15-22 (now applicable to claims 15-17, 20-21, 23-36) under
`
`35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement is
`
`maintained for reason of record and claims 16, 23-35 are rejected also for containing new matter.
`
`Applicants pointed to table 10 as the antecedent basis for the claimed products.
`
`Lupin Ex. 1011 (Page 3 of 9)
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`

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`Application/Control Number: 12/536,807
`Art Unit: 1625
`
`Page 3
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`It is clearly described that table 10 is "expected mass losses" that is it is a calculated loss if such
`
`mass was found in theremogravimetric experiments. The experimental results for example
`
`were:
`
`range: 2fi,-1 I(F C, (:~N~fbr ’i?:x’78~’ C0, gr~m I I {b
`
`The specification has not provided any product that showed water loss co~esponding to the
`
`above table or to the claims i.e. a continuous range between 0.5-3 molecules of water per
`
`molecule of the compound. This is Nrther evidenced by the structural delineation of the
`
`products of the instant application being indexed by CAS wherein a 1" 1 ratio ethanolate was
`
`indexed with other solvateNydrate being of indefinite ratio (see CA140).
`
`Therefore, the explicit compounds having l:0.5m 1:2, 1:3 etc. are new matter for which
`
`no antecedent basis of possession was found.
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`Lupin Ex. 1011 (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.
`
`The rejection of claims 15-22 (now applicable to claims 15-17, 20-21, 23-36) under 35
`
`U.S.C. 112, first paragraph, as failing to comply with the enablement requirement is maintained
`
`for reason of record.
`
`The Wands analysis in the record is as following:
`
`Nature of 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-aminophenyl)sulfonyl] (isobutyl) aminol-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 of 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.
`
`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.
`
`Lupin Ex. 1011 (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 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).
`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]-l-
`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
`llO-200°C further 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
`solvate/hydrate 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
`solvate/hydrate, 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
`
`Lupin Ex. 1011 (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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`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 7Oral
`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
`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 7Oral
`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
`llO-200°C further 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)-
`
`Lupin Ex. 1011 (Page 7 of 9)
`
`

`
`Application/Control Number: 12/536,807
`
`Art Unit: 1625
`
`Page 7
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`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 steps 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.
`
`Applicants pointed to examples 2, 4, 7, 11, 12 and tables 10, 18 etc. as support for hemi-,
`mono-, di- or tri-hydrates finds no enabling support for the description because as it was
`indicated supra that the experimental "loss" does not meet the expected loss and repeatedly the
`specification explained that the discrepancy is because the loss is water+solvent not water alone.
`
`The publication of Gyseghem et al. is hereby provided for applicants’ convenience for
`which a corresponding meeting abstract was provided previouly. The full article evidenced that
`the (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 (TNC 114) is a channel hydrate which
`is an inclusion compound in crystalline state. Inclusion compound can have various
`solvent/water entrapment with a range of solvent/water content that stabilized the channel crystal
`(see p.497).
`
`In the specification, p.23-24, example 4, The TG data indicated the "loss" is a
`combination of water and solvent without clearly identifying the molecular composition of such
`products. Were they inclusion product of (3 R,3aS,6aR)- hexahydrofuro [2,3-b] furan-3-yl (1
`S ,2R)-3- [ [(4- aminophenyl) sulfonyl] (isobutyl) amino] -1-benzyl-2- hydroxypropyl carbamaterin,
`Then, they are the same crystalline host with different guest molecules, thus, is one product with
`variation of inclusion (see for example Gao et al. known compound warfarin sodium). Further,
`for inclusion compounds products with different inclusion would have one/similar x-ray
`diffractogram. In the specification, there is disclosed only one x-ray diffraction pattern (fig. 1-3
`of form A only) which corresponding to ethanolate in a 1:1 ratio. Were the other forms each is
`a different crystal 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 and solvent
`addition, then, there is no clear description of the molecular ratio of the "compounds" or how
`such hemi- mono- di- or tri-hydrate was made which was further evidenced by the CA
`delineation.
`
`5.
`
`Applicant’s amendment necessitated the new grounds of rejection presented in this Office
`
`action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is
`
`reminded of the extension of time policy as 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
`
`Lupin Ex. 1011 (Page 8 of 9)
`
`

`
`Application/Control Number: 12/536,807
`
`Art Unit: 1625
`
`Page 8
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`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 date of this
`final action.
`
`6. 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
`May 15, 2012
`
`/Celia Chang/
`Primary Examiner
`Art Unit 1625
`
`Lupin Ex. 1011 (Page 9 of 9)