Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 1 of 328 PageID #: 2678
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`Plaintiffs,
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`
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`v.
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`
`
`Defendant.
`
` C.A. No. 17-cv-868-CFC-SRF
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`
`UNIVERSITY OF MASSACHUSETTS
`and CARMEL LABORATORIES, LLC,
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`L’ORÉAL USA, INC.,
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`JOINT CLAIM CONSTRUCTION BRIEF
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`JOINT CLAIM CONSTRUCITON
`APPENDIX
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`JOINT CLAIM CONSTRUCTION
`APPENDIX
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`

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`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 2 of 328 PageID #: 2679
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`JOINT APPENDIX OF EVIDENCE
`University of Massachusetts, et al v. L’Oréal USA, Inc.
`17-cv-868-CFC-SRF
`
`
`
`Appx No.
`Description of Document
`A0001-008
`Excerpts of the file history of U.S. Pat. App. No. 09/179,006
`Excerpts of the file history of the '327 Patent, including Applicants’
`A0009-104
`translation of German Patent Application DE 195 45 107 A1
`A0105-145
`Excerpts of the file history of the '513 Patent
`A0146-170
`Excerpts of the file history of U.S. Pat. App No. 10/680,370
`Decision Denying Institution of Inter Partes Review of the '327 Patent A0171-191
`Decision Denying Institution of Inter Partes Review of the '513 Patent A0192-211
`Decision Denying Petitioner’s Request for Rehearing for the '327 Patent A0212-223
`Decision Denying Petitioner’s Request for Rehearing for the '513 Patent A0224-235
`Excerpts of ’327 IPR Patent Owner Preliminary Response
`A0236-238
`Declaration of Professor Gerald B. Kasting, Ph.D. and curriculum vitae A0239-289
`Hartzshtark et al., “The Use of Indentometry to Study the Effect of
`Agents Known to Increase Skin c-AMP Content,” Experientia 41
`(1985): 378, Birkhauser Verlag, CH 4010 Basel/Switzerland
`Excerpts of C.L. Baer & B.R. Williams, Clinical Pharmacology and
`Nursing (1996)
`OECD Guidelines for the Testing of Chemicals, Section 4, Test No.
`411: Subchronic Dermal Toxicity: 90-day Study (1981)
`Excerpts of R. Woodrow, Essentials of Pharmacology for Health
`Occupations (1997)
`Excerpts of Physicians’ Desk Reference (1996)
`February 2020 email chain between counsel regarding expert
`depositions
`
`A0290-292
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`A0293-298
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`A0299-309
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`A0310-327
`A0328-339
`A0340-343
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`Tab
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`15
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`

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`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 3 of 328 PageID #: 2680
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 3 of 328 PageID #: 2680
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`TAB 01
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`A0001
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`TAB 01
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`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 4 of 328 PageID #: 2681
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 4 of 328 PageID #: 2681
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`Attorney Docket No.: a, 917-045001 /(UMMC 97-32)
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`Qiélf
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`é
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`MD STATES PATENT AND TRADEMARK OFFICE
`:
`James G. Dobson et 31.
`ArtUnit
`: 1615
`: October26, 1998
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`Serial No.
`
`Applicant
`Filed
`
`Title
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`: 09/179,006
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`Examiner : Charmavajjala
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`: TREATMENT OF SKIN WITH ADENOSINE OR ADENOSINE ANALOG
`
`I 7,’ /
`9
`04%
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`—‘ '1
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`5".
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`r ...
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`0“
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`to
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`Assrstant Comm1ss1oner for Patents
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`‘Washington, DC. 20231
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`‘ 5,
`...TJ
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`/
`4:1
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`,.
`Cancel claims 9, 11-29, 37, 46 and 48-53.
`f
`Amend claims 1, 30 and 39 as follows:
`:
`e
`1. (Amended) A method for [enhancing the condition] reduc‘in wrinklin
`rou
`ess
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`gmess, laxity or sallowness of non-diseased unbroken skin of a mammal, comprising
`[topically] applying a [therapeutically] patch comprising an effective amount ofa composition
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`comprising adenosine or an adenosine receptor agonist to flip non-diseased unbroken skin of
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`U w
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`(
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`30. (Amended) A method for increasing protein synthesis in a [dermal cell of] fibroblast
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`i_n non-diseasedz unbroken skin of a mammal, comprising [topically administering] applying to a
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`region of the skin containing the fibroblast a patch comprising an [a therapeutically] effective
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`amount of adenosine or an adenosine receptor agonist [to a region of non-diseased skin of said
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`9/
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`CERTIFICATE OF MAILING BY FIRST CLASS MAIL
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`I hereby certify under 37 CFR §1.8(a) that this correspondence is being
`deposited with the United States Postal Service as first class mail with
`sufi'icient postage on the date indicated below and is addressed to the
`Assistant Co
`'ssioner for Patents, Washington, DC. 20231.
`
`Enid/vole 3, 2000
`Date ofDeposit :
`2
`Signature
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`'
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`bi ADE CALPWT'E'P‘
`Typed or Printed Name of Person Signing Certificate
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`A0002
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`,
`In response to the action mailed December 22, 1999, please amend the application;as’ ,
`follows:
`475
`if;
`a : 3
`{33
`? 1
`1'3
`,
`,__ D
`I
`m
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`In the Claims:
`—_
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`v1”I’m,‘-
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`

`

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`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 5 of 328 PageID #: 2682
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 5 of 328 PageID #: 2682
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`Applicant
`Serial No.
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`Attorney DocketNo.: s 917-045001/(UMMC97-32)
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`mammal containing said dermal cell, wherein addition ofsaid adenosine does not cause
`fl/
`proliferation of said dermal cell].
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`39. (Amended) A method for increasing cell size [in a dermal cell] of fibroblast in non-
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`9 (diseased unbroken skin ofa mammal, comprising [topically administering] applying to a region
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`of the skin containin the fibroblast a atch com risin an [a therapeutically] effective amount of
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`adenosine or an adenosine recpptor agonist [to a region of non-diseased skin of said mammal
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`containing said dermal cell, wherein addition of said adenosine does not cause proliferation of
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`~—+
`said dermal cell].
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`‘ .J z
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`i. "3
`-..~
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`Lil—it".f‘.
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`Claims 1-10 and 30-47 are pending, claims 11—29 and 48-53 having been cancelled.
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`Remarks
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`35 USC 112
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`\
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`L5,;
`S:-‘
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`Claims 21, 30 and 39 stand rejected under 35 USC § 112, first paragraph, as allegedly
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`nonenabled. More particularly, the Office action states:
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`[T]he specification, while being enabling for treating fibroblasts with adenosine to
`increase DNA synthesis, protein synthesis and increase cell size does not
`reasonably provide enablement for other dermal cells as claimed.
`The instant
`claims are directed to increasing DNA synthesis, protein synthesis or cell size in V
`dermal cells. However, the specification provides data only with fibroblasts from
`skin and not from any other cell types.
`[I]t is well known from the anatomical
`structure, skin comprises several types of cells .. ..
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`Applicant has clarified claims 30 and 39 by amending them to specify that the increased
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`protein synthesis and increased cell size (respectively) occur in a “fibroblast” in the skin rather
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`than “a dermal cell.” This overcomes the rejection (Claim 21 having been cancelled).
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`Claims 1-53 stand rejected under 35 USC § 112, second paragraph for alleged lack of
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`clarity. More particularly, the Office action states:
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`Claims 1 and 48 recite “method of enhancing” skin condition, which is vague
`because it is not clear as to enhance from What and to achieve what effect. A
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`correction and clarification is requested. From claims 1-53, it is unclear why a
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`A0003
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`

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`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 6 of 328 PageID #: 2683
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 6 of 328 PageID #: 2683
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`Attorney Docket No.: c I917-045001 / (UMMC 97—32)
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`therapeutically effective amount of adenosine is required when there is no disease
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`being treated for.
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`Cancellation of claims 11-29 and 48-53 renders the rejection moot with respect to those
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`claims.
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`Applicant has clarified claim 1 by amending it to recite “reducing wrinkling, roughness,
`dryness, laxity or sallowness” ofthe skin, instead of “enhancing the condition” of the skin.
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`Support for this amendment appears in the specification, e.g., at page 4, lines 3—6 and 13—15.
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`Therefore, the amendment does not introduce new matter. This amendment fully addresses the
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`“enhancing the condition” aspect of the rejection.
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`Applicant has amended claims 1, 30 and 39 to recite “effective amount” instead of
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`“therapeutically effective amount.” This amendment merely deletes an unnecessary word, and
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`does not change the meaning or scope of the claim. Therefore, the amendment does not
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`introduce new matter. This amendment fully addresses the “therapeutically effective amount”
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`aspect of the rejection. ‘
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`The above amendments overcome the rejection.
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`35 USC § 102
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`Claims 1, 3-5 and 10 stand rejected under 35 USC § 102(b) as allegedly anticipated by
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`Stramentinoli et al., US. Patent No. 4,454,122. More particularly, the Office action states:
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`[Stramentinoli] ’122 teaches adenosine or adenosine derivatives for the treatment
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`of inflammation or as analgesic or antipyretic (see col. 1, 3). Although the
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`reference does not explicitly mention skin treatment, the teaching of external use
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`by topical application (col. 11 and 12) includes skin. Further, although the
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`[reference] does not mention non-diseased skin, analgesia (defined as sense of
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`pain) and inflammation (defined as local response to injury) are not always
`associated with a disease.
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`Applicant traverses this rejection. Contrary to the examiner’s statement, Stramentinoli
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`does not teach the use of adenosine for the treatment of inflammation or as an analgesic or
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`antipyretic. The Stramentinoli disclosure is limited to certain sulfur-containing derivatives of
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`adenosine. Moreover, Stramentinoli does not indicate that the disclosed, sulfur-containing
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`A0004
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`

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`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 7 of 328 PageID #: 2684
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 7 of 328 PageID #: 2684
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`AppliCant
`Serial No.
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`Attorney Docket No.: 07917—045001 / (UMMC 97-32)
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`derivatives are agonists of any type of adenosine receptor. Consequently, Stramentinoli lacks
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`relevance to the present claims. Therefore, the rejection should be withdrawn.
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`Claims 1, 3—8 and 10 stand rejected under 35 USC § 102(c) as allegedly anticipated by
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`Manneth et al., US Patent No. 5,998,423 or Cronstein et a1., US. Patent No. 5,932,558. More
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`particularly, the Office action states:
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`[Manneth]‘423 teaches compositions comprising adenosine, cyclohexyladenosine
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`or cyclopentyladenosine and their use for the modulation of melanin production in
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`the skin and hair and in enhancing the tanning process and providing protection
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`for the skin against UV radiation (see col. 1, lines 7-13; col. 2, lines 44-63).
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`[Cronstein] ‘558 teaches composition comprising adenosine agonists for
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`the healing wounds, burns (abstract, lines bridging col. 3 and 4) by promoting
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`influx of fibroblasts and epithelial cells (col. 4).
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`As presently amended, claim 1 requires “applying to the unbroken skin a patch
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`comprising an effective amount of a composition comprising adenosine or an adenosine receptor
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`agonist.” Support for the amendment appears in the specification, e.g., at page 9, lines 29-31
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`(transdermal patch). Support for the amendment also appears in the specification at page 6, lines
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`22, 28 and 33, and page 7, line 1 (“adenosine receptor agonist,” instead of “adenosine agonist”).
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`The specification discloses using adenosine or an adenosine receptor agonist to enhance the
`condition ofnon-diseased skin, e.g., at page 2, 1ines7-9, and to decrease wrinkling or roughness,
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`e.g., at page 13-15. This constitutes a clear disclosure of the use of these agents on unbroken
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`skin, thereby fully supporting amendment of claim 1 to recite “unbroken” skin.
`Manneth does not teach administering adenosine or an adenosine receptor agonistby
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`incorporating it into a patch. Indeed, a person following the teaching ofManneth would be
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`motivated not to administer adenosine or an adenosine receptor agonist by means of a patch,
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`because melanin production, i. e., tanning, because tanning only in isolated spots or areas of skin
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`would be unsightly and undesirable. Therefore, Manneth lacks relevance to amended claim 1.
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`The Cronstein disclosure is limited to the use of an adenosine receptor agonist to promote
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`healing of a wound or burn, i.e., applying a composition containing an adenosine receptor
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`agonist to broken skin. In contrast, claim 1 specifies applying a patch containing adenosine or an
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`adenosine receptor agonist to unbroken skin. Therefore, Cronstein lacks relevance to amended
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`claim 1.
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`A0005
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`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 8 of 328 PageID #: 2685
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 8 of 328 PageID #: 2685
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`Applicant
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`: 5
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`Attorney Docket No.: 07917-045001 / (UMMC 97-32)
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`Claims 1-20 stand rejected under 35 USC § 102(a) as allegedly anticipated by von
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`Borstel et al., US. Patent No. 5,770,582. More particularly, the Office action states (emphasis
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`added):
`[Von Borstel] ‘582 teaches Myribonucleosides such as 2’-deoxyadenosine for
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`accelerating the healing of wounds, cuts, abrasions and ameliorate the effects of
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`aging. ‘582 teaches angiogenic factors, growth factors such as fibroblast growth
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`factor and other additives for topical application. .. . [W]ounds, cuts, [and]
`abrasions involve broken skin.
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`Applicants traverse this rejection. The van Borstel teaching relates to
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`Myribonucleosides, not ribonucleosides. In contrast, applicant’s claims require application of
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`adenosine or an adenosine receptor agonist. Adenosine is a ribonucleoside, not a
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`deoxyribonucleoside. The two classes of compounds differ structurally and are quite distinct in
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`their chemical and biological properties. The structural difference is well known. See, e.g.,
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`Lehninger, Biochemistry (2nd Ed.), Worth Publishers, New York (1975), at page 310 (copy
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`enclosed). Deoxyribonucleosides would not be expected to bind to adenosine receptors so as to
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`elicit a biological response, and thus, the deoxyriboncleosides taught by von Borstel are not
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`adenosine receptor agonists. See, e.g., Wolff et al., Adv. Cyclic Nuc. Acids Res. 14:199-214
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`(l981)(copy enclosed). While applicant’s method claims involve the use of one class of
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`compounds, von Borstel relates to a different class of compounds.1 For this reason, and contrary
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`to the examiner’s contention, von Borstel clearly lacks relevance to applicants’ claims.
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`Therefore, the rejection should be withdrawn.
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`35 USC§103(a)
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`Claims 1-8 and 10 stand rejected under 35 USC § 103(a) for alleged obviousness over
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`Stramentz‘noli, Manneth or Cronstez'n. In particular, the Office action asserts that claim
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`recitations regarding molar concentrations, failure to cause cell proliferation or inclusion of
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`1 Applicant recognizes that at page 6, line 17 the specification refers to 2’-deoxyadenosine as an “agonist of
`adenosine.” However, the pending claims specify use of an “adenosine receptor agonist,” in contrast to an
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`“adenosine agonist.” The specification clearly gives those two terms distinct meanings. For example, at page 6,
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`lines 12-16, those terms are listed as two separate subcategories under the more general category “adenosine
`analog.” Thus, although the specification lists 2’-deoxyadenosine as an adenosine analog, the specification does not
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`state or otherwise indicate that 2’-deoxyadenosine or any other deoxyribonucleOSide is an “adenosine receptor
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`agonist,” which is what the claimed methods explicitly require.
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`A0006
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`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 9 of 328 PageID #: 2686
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 9 of 328 PageID #: 2686
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`
`
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`Applicant
`Serial No.
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`
`Filed
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`Page
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`
`: Dobson etal.
`: 09/179,006
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`: October 26, 1998
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`: 6
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`Attorney Docket No.: U7917-O45001/(UMMC97-32)
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`angiogenic components do not suffice to distinguish the claimed invention over the cited
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`references. These assertions are rendered moot by the present amendments and the resulting
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`distinctions discussed above. Therefore, the rejection should be withdrawn.
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`Claims 1-20 and 48-53 stand rejected under 35 USC § 103(a) for alleged obviousness
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`(over von Borstel. For the reasons explained above, von Borstel lacks relevance to the claimed
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`methods. Therefore, the rejection should be withdrawn.
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`Claims 21-47 stand rejected under 35 USC § 103(a) for alleged obviousness over
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`Stramentinoli, Manneth, Cronstein or van Borstel in View of Ahmed et al., Biochem. Biophys.
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`Res. Commun. 208:871-878, 1995. More particularly, the Office action states (emphasis added):
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`Ahmed et a1 teaches adenosine stimulates DNA synthesis in human foreskin
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`fibroblasts as measured by thymidine incorporation. Although none of the
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`references teach protein synthesis and increase in cell size with adenosine, it is
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`the position of the examiner that it is well known during in [sic] a cell cycle,
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`typically a cell undergoes mitotic or resting phase and DNA synthesis occurs
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`during resting phase. It is in the resting phase that a cell prepares for mitosis by
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`increasing the process of translation, protein synthesis followbd by increase in
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`contents of cell (cell size), before entering the mitotic phase (proliferation).
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`Applicants traverse this rejection with respect to claims 30—47, which relate to increasing
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`protein synthesis or increasing cell size. The Office action concedes that “none of the references
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`teach [increase in] protein synthesis and increase in cell size with adenosine.” There are at least
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`two fatal flaws in the rejection.
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`First, the examiner’s contention that increased protein synthesis and increased cell size
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`necessarily follow from increased DNA synthesis is highly speculative, and unsupported by
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`citation of any specific reference whatsoever from the prior art. A proper obviousness rejection
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`must be based on more than such a mere unsupported conclusion by the examiner. Furthermore,
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`the examiner’s reasoning postulates mitotic activity, i.e., cell proliferation, and applicant’s
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`specification explicitly states that the invention works without stimulation of cell proliferation
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`(page 2, lines 31-33): “The adenosine or adenosine analog does not cause proliferation of the
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`dermal cell.”
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`Second, where the rejection is based on a combination of references, the examiner has the ~
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`burden of showing a that a person of ordinary skill in the art would have been motivated to
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`A0007
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`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 10 of 328 PageID #: 2687
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 10 of 328 PageID #: 2687
`
`Applicant
`SerialNo.
`Filed
`Page
`
`: Dobson ct a1.
`: 09/179,006
`: Octobcr26,1998
`: 7
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`Attorney DockctNo.: U7917-045001/(UMMC 97-32)
`
`combine the references so as to arrive at the invention - with the motivation coming from the
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`prior art - not applicant’s own teaching. It is well established that hindsight reconstruction using
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`the application as a template is improper and impermissible. In re Gorman, 933 F.2d 982, 18
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`‘USPQ2d 1885 (Fed. Cir. 1991). Moreover, to the extent that the rejection rests on von Borstel,
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`the rejection fails, because as applicant explains above, von Borstal teaches a class of compounds
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`different from the genus of compounds specified by the pending claims.
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`For the foregoing reasons, the rejection of claims 30-47 is unsound and should be
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`withdrawn. Cancellation of claims 21-29 renders the rejection moot with respect to those claims.
`
`Conclusion
`
`Applicant submits that all of the claims are now in condition for allowance, which action
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`is requested. Please apply any other charges or credits to Deposit Account No. 06-1050.
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`Respectfully submitted,
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`fig: {1%
`
`Gary L. Creason
`Reg. No. 34,310
`
`Date: 0? MARCH 2000
`
`Fish & Richardson RC.
`225 Franklin Street
`
`Boston, MA 02110-2804
`Telephone: (617) 542-5 070
`Facsimile: (617) 542-8906
`
`20017979.doc
`
`A0008
`
`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 11 of 328 PageID #: 2688
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 11 of 328 PageID #: 2688
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`TAB 02
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`A0009
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`TAB 02
`
`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 12 of 328 PageID #: 2689
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`PAGES A0010 – A0027
`INTENTIONALLY LEFT BLANK
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`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 13 of 328 PageID #: 2690
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 13 of 328 PageID #: 2690
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`Attomey’s Docket
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`07917-045002 ) (UMMC 97-32)
`
`APPLICATION
`
`,
`
`FOR
`
`UNITED STATES LETTERS PATENT
`
`TITLE:
`
`TREATMENT OF SKIN WITH ADENOSINE OR
`
`ADENOSINE ANALOG
`
`APPLICANT:
`
`James G. Dobson and Michael F. Ethier
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`Iii-‘2if;“:33{Ea[J
`
`HHE‘JETU°'EMT
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`E H
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`CERTIFICATE OF MAILING BY EXPRESS MAIL
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`ExprssMnilIAbelNo. EL zfl9‘IBIOSG Q;
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`.
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`‘
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`I hereby certify under 37 CFR §l.10 that this correspondence is being
`deposited with the United States Postal Service as Express Mail Post
`Office to Addressee with sufficient postage on the date indicated below
`and is addrmsed to the Commissioner
`for Patents, Washington,
`DC. 20231.
`
`
`
`Signature
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`M
`Typed or Prinwd Name of Person Signing Certificate
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`9/156
`
`A0028
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`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 14 of 328 PageID #: 2691
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 14 of 328 PageID #: 2691
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`
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`ATTORNEY DOCKET NO: 07917/045002
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`PATENT
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`TREATMENT OF SKIN WITH ADENOSINE OR ADENOSINE ANALOG
`NS :1
`atement as to Federally Sponsored Research
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`C;
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`Work on this invention was supported by funds from
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`the United States government
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`(Public Health Service Grants
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`HL-22828 and AG-11491).
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`The government therefore has certain
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`10
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`rights in this invention.
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`15
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`20
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`25
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`"h
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`EéflwfifiififlflI \
`HHHfiflfl”fl
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`Field of the Invention
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`This invention relates to dermatology and cell
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`biology.
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`Background of the Invention
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`Skin includes a surface layer, known as the
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`epidermis, and a deeper connective tissue layer, known as the
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`dermis.
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`The epidermis undergoes continuous turnover as the
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`outermost cells are exfoliated and replaced by cells that
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`arise from inner dermal layers.
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`The dermis is composed of a
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`variety of cell types,
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`including fibroblasts.
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`Skin thickness begins to decline in humans after the age
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`of 20 as the dermis becomes thinner and the number of skin
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`fibroblasts declines. As skin ages, or is exposed to UV
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`light and other environmental insults, changes in the
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`underlying dermis can lead to the functional and
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`morphological changes associated with damaged skin.
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`Decreases in the abundance and function of products of the
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`30
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`fibroblasts, which include collagen and proteoglycans, are
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`believed to play major roles in wrinkled and damaged skin.
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`10/156
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`A0029
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`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 15 of 328 PageID #: 2692
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 15 of 328 PageID #: 2692
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`
`
`Summary of the Invention
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`We have discovered that adenosine stimulates DNA
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`synthesis,
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`increases protein synthesis, and increases cell
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`size in cultures of human skin fibroblasts. Based on this
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`discovery,
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`the invention provides methods and compositions
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`for enhancing the condition of skin.
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`‘
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`In general,
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`the invention provides a method for
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`enhancing the condition of non-diseased skin of a mammal,
`
`10
`
`The method includes topically applying a
`e.g., a human.
`therapeutically effective amount of a composition including
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`adenosine or an adenosine analog to non-diseased skin of the
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`mammal.
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`.
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`The invention also provides a method for promoting
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`healing of broken, non-diseased skin in a mammal by
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`15
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`topically administering a composition including a
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`therapeutically effective amount of adenosine or an
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`adenosine analog to the mammal.
`
`Also included in the invention is a method for
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`increasing DNA synthesis in a dermal cell of non-diseased
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`2.0
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`skin of a mammal.
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`The method includes topically
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`administering a therapeutically effective amount of
`
`adenosine or an adenosine analog to a region of non-diseased
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`skin of the mammal containing dermal cell.
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`The adenosine is
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`added so that it does not cause proliferation of the dermal
`
`25
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`cell.
`
`The invention also features a method of increasing
`
`protein synthesis in a dermal cell of non-diseased skin of a
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`mammal.
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`The method includes topically administering a
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`composition including a therapeutically effective amount of
`
`30
`
`adenosine or an adenosine analog to a region of skin of the
`
`mammal containing the dermal cell.
`
`The adenosine or
`
`adenosine analog does not cause proliferation of the dermal
`cell.
`
`.. Ll
`
`Eflfiflfl
`flflfiflfifl“flh$
`
`\
`
`\.\/
`
`A0030
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`11/156
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`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 16 of 328 PageID #: 2693
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 16 of 328 PageID #: 2693
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`Also provided in the invention is a method of
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`increasing cell size in a dermal cell in non—diseased skin
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`of a mammal, e.g., a human.
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`The method includes topically
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`administering a composition including a therapeutically
`
`effective amount of adenosine to a region of skin of the
`
`mammal containing the dermal cell, wherein addition of the
`adenosine does not cause proliferation of the dermal cell,
`
`wherein addition of the adenosine does not cause
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`proliferation of the dermal cell.
`
`The invention also includes a method for enhancing
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`skin condition in a mammal, e.g., a human.
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`The method
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`includes providing fibroblasts from the mammal ex vivo,
`culturing the fibroblasts in the presence of adenosine, and
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`reintroducing the
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`fibroblasts into the mammal.
`
`The therapeutically effective amount of adenosine
`used in the above-described methods is preferably‘IO'3 M to
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`10'7 M, more preferably 10“ M to 10'6 M, and most preferably'
`
`about 10“ M.
`
`The composition used in the above-described methodsr
`
`can include a second agent in addition to adenosine.
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`The
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`seCOnd agent can be, e.g. an agent that promotes binding of
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`adenosine or an adenosine analog to an adenosine receptor,
`an angiogenic factor such as vascular endothelial cell
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`growth factor (VEGF), basic fibroblast growth factor (BFGF),
`
`an agent that itself enhances skin condition, such as
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`tretoinin or another known conditioning agent such as an
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`emollient, a humectant, or an occlusive agent.
`
`In preferred embodiments of the invention,
`
`the
`
`adenosine or an adenosine analog does not promote skin cell
`
`10
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`15
`
`20
`
`25
`
`.flmflflflmmflhfififlflflfl
`
`30
`
`proliferation.
`
`The invention also provides a composition including
`about-10‘3 M to about 10‘7 M adenosine and a therapeutically
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`effective amount of an angiogenesis factor.
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`In some
`
`- 3 -
`
`12H56
`
`A0031
`
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`
`
`
`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 17 of 328 PageID #: 2694
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 17 of 328 PageID #: 2694
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`.uzr"?.957.29:21523.1111}:
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`
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`.Eimfi7{!
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`embodiments,
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`the composition of the adenosine is about 10‘4
`
`M.
`
`,.
`As.used herein,
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`"enhancement of skin condition"
`
`_
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`means a noticeable decrease in the amount of wrinkling,
`roughness, dryness, laxity, sallowness, or pigmentary
`
`mottling in skin.
`
`As used herein, a "therapeutically effective amount"
`
`of adenosine or an adenosine analog means an amount that
`enhances skin condition when applied to skin.-
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`As used henein,
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`"non—diseased skin" means skin free
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`of any proliferative disorder observable by visual
`inspection.
`i
`
`The present invention advantageously allows for
`
`enhancement of skin condition. This results in skin that
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`shows a less wrinkled,
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`rough, or dry complexion.
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`For
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`example,
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`the invention provides for enhancing the condition
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`of skin damaged due to exposure to the sun or skin whose
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`condition has deteriorated due to normal aging.
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`Unless otherwise defined, all technical and
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`scientific terms used herein have the same meaning as.
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`commonly understood by one of ordinary skill in the art to
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`which this invention belongs. Although methods and
`
`materials similar or equivalent to those described herein
`
`can be used in the practice or testing of the present
`
`invention, suitable methods and materials are described
`
`below. All publications, patent applications, patents, and
`
`other references mentioned herein are incorporated by
`
`reference in their entirety.
`
`In case of conflict,
`
`the
`
`present specification,
`
`including definitions, will control.
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`In addition,
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`the materials, methods, and examples are
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`illustrative only and not
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`intended to be limiting.
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`10
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`H U'I
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`20
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`30
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`’’’’’’
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`13/156
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`A0032
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`53!333i1E2?242??!5351:m"'
`
`

`

`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 18 of 328 PageID #: 2695
`Case 1:17-cv-00868-CFC-SRF Document 98 Filed 03/06/20 Page 18 of 328 PageID #: 2695
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`
`Other features and advantages of this invention will
`be apparent from the following description of the preferred
`embodiments thereof, and from the claims.
`
`g Brief Description of the Drawings
`
`Figs. 1A and 1B are histograms showing the effect of
`adenosine on PHJthymidine incorporation in cultures of
`
`normal human skin (Fig. 1A) and lung fibroblaSts (Fig. 13).
`
`After incubation in serum-free medium for 24 hours, cells
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`were exposed to 10* M adenosine for 18 hours. Medium was
`replaced with serum-free medium without adenosine, and
`
`16
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`PH1thymidine was added. Results are expressed as percent
`
`PHJthymidine incorporation compared to control_cultures
`without adenosine and are means i SEM for 4-5 experiments.
`"*" denotes value was significantly different from-control
`
`15
`
`value without adenosine.
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`20
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`25
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`3O
`
`Figs. 2A and 2B are histograms showing concentration
`
`responses of adenosine-stimulated protein synthesis in human
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`skin fibroblasts from a young (Fig. 2A) and aged (Figl 28)
`
`donor. Cells were gr