Case 1:17-cv-00868-VAC-SRF Document 10-1 Filed 08/04/17 Page 1 of 9 PageID #: 179
`Case 1:17-cv—00868—VAC-SRF Document 10-1 Filed 08/04/17 Page 1 of 9 PagelD #: 179
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`
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`EXHIBIT A
`EXHIBIT A
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`

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`Case 1:17-cv-00868-VAC-SRF Document 10-1 Filed 08/04/17 Page 2 of 9 PageID #: 180
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`Attorney's DocketN" . <07917·045002/ (UMMC97-32)
`\
`
`Applicant
`
`Serial No.
`Filed
`Title
`
`I .
`
`,
`
`~
`HE UNITED STATES PATENT AND TRADEMARK OFF~
`~a
`~ ~ ~
`Art Unit
`: 1615
`James G. Dobson, Jr. and
`Examiner: L. Channavajjala ~ &.> ~
`Michael F. Ethier
`~ ~ ' ( )
`..
`09/672,348
`. {jJ
`P
`September 28, 2000
`TREATMENT OF SKIN WITH ADENOSINE OR ADENOSINE ANALOG ~
`~
`/() / (!, #djL
`. I ~ C?{E)
`
`BOXAF
`Commissioner for Patents
`Washington, D.C. 20231
`
`RESPONSE TO FIN'AL OFFICE ACTION DATED OCTOBER 10,2001
`
`PURSUANT TO 37 C.F.R. 1.1l6(A)
`
`Please amend the application as indicated below, and consider the following remarks.
`
`I
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`In the claims
`
`/
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`/
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`Cancel claims 54 to?ithout prejudice as directed to a non-elected invention.
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`Amend claim 70 as follows.
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`:
`1
`-ixf. (Amended) A method for enhancing the condition of unbroken skin of a mammal by
`reducing one or more of wrinkling, roughness, dryness, or laxity of the skin, without increasing
`
`dermal cell proliferation, the method comprising topically applying to the skin a composition
`
`comprising a concentration of adenosine in an amount effective to enhance the condition of the
`
`skin without increasing dermal cell proliferation, wherein the adenosine concentration applied to
`the dermal cells is 10-4 M to 10-7 M.
`
`\
`
`CERTIFICA IE OF MAILING BY FIRST CLASS MAIL
`
`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
`sufficient postage on the date indicated below and is addressed to the
`
`C(d12VW2::1ingti D.C.~~ .
`
`s;ttzwqt
`
`Typed or Pnnted Name of Person Signing Certificate
`
`Slgnate ~
`t-4~aL2' Gra~
`
`c
`
`

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`Case 1:17-cv-00868-VAC-SRF Document 10-1 Filed 08/04/17 Page 3 of 9 PageID #: 181
`
`App,licant :
`Ethier
`Serial No. :
`Filed
`Page
`
`James G. Dobson, ',' and Michael F.
`
`Attorney's Docke~, ,,'.: 07917-045002/ (UMMC 97-
`32)
`
`09/672,348
`September 28, 2000
`2
`
`REMARKS
`
`Claims 70 to 79 are pendin.g in this application. Applicants propose canceling daims 54
`
`to 69 as allegedly directed ,to a non-elected invention. Applicants also propose to amend claim
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`70. This amendment would add no new matter, as it merely includes a range of concentrations
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`of adenosine recited in dependent claims and in the specification at page 3, lines 15-18.
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`In addition, the amendment set forth above would raise no new issues that would require
`, .
`further consideration and/or search. Applicants submit that this amendment would place the
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`'
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`claims into condition for allowance, or at least present the rejected claims in better form for
`
`consideration on appeal, and sh<mld therefore be entered after the final rejection under 37 C.F.R.
`
`§ 1.116 (a).
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`Restriction
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`Applicants disagree with the Examiner's conclusion that' the present claims 54 to 69 are
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`directed to a separate invention than that claimed in claims 70 to 79, because all are based on the
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`application of certain: concentrations of adenosine to the skin to achieve certain results.
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`Nevertheless, applicants propose to cancel these claims as directed to a non-elected invention
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`unless the Examiner reconsiders and withdraws this restriction. Thus, claims 70 to 79 would be
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`pending.
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`35 U.S.C. § 112, First Paragraph
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`Claims 70 to 79 have been rejected as allegedly containing subject matter that was not
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`described in the specification in such a way as to enable one skilled in the art to make and/or use
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`the invention. Applicants traverse this rejection in view of experimental test results as described
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`in a declaration (attached hereto) by the two co-inventors of this application, Dr. James G.
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`Dobson, Jr. and Dr. Michael F. Ethier ("the Declaration").
`
`According to the Office Action, applicants state that adenosine does not cause cell
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`proliferation of dermal cells, but the application provides no experimental evidence to show
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`whether there is an increase or decrease in the cell proliferation. Applicants now provide that
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`evidence. As described in the Declaration, applicants conducted tests of skin fibroblast cells, c
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`

`

`Case 1:17-cv-00868-VAC-SRF Document 10-1 Filed 08/04/17 Page 4 of 9 PageID #: 182
`
`Applicant: .James G. Dobson,.. .... and Michael F.
`Ethier
`Serial No. : 09/672,348
`Filed
`September 28, 2000
`3'
`Page
`
`Attorney's Docket, ,0.: 07917-0450021 (UMMC 97-
`•
`3~
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`which make up a significant portion of dermal cells, from two different donors (an 84 year-old
`man and 30 year-old female), with varying concentrations of adenosine (10-4 or 10-5 M). The
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`added adenosine had no significant effect on cell proliferation over a 5 day period, i.e." the
`adenosine did not increase cell proliferation at concentrations of 10-4 or 10-5 M (see Declaration,
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`paragraph 3).
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`Although applicants believe that claim 70 as written covers this result by functional
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`.
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`language, in the interests of moving this application towards allowance, they have proposed to
`
`amend claim 70 to reflect this experimental result. Based on this new information, applicants
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`request the Examiner to reconsider and withdraw this rejection under Section 112, first
`
`paragraph.
`
`As for the Office's assertion that "it is well ,known in the art that adenosine stimulates
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`proliferation of cells, such as endoth~lial cells or in particular cells in the skin" based on German
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`patent DE 19545107, applicants will discuss this reference in more detail below in relation to the
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`alleged anticipation.
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`35 U.S.C. § 102
`
`Claims 70, 74 to 76, and 78 have been rejected as allegedly anticipated by DE 19545109
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`(the German patent application). Applicants traverse this rejection in view of the ne,w data
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`described in the enclosed Declaration.
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`According to the Office Action, the German patent application "discloses a cosmetic and
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`dermatological preparation containing adenosine for the treatment of natural, chemical induced
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`or UV -induced skin aging and its sequelae. While DE states that adenosine stimulates cell
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`proliferation, DE does not state that adenosine increases cell proliferation .. ,. Accordingly, DE
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`anticipates the instant method" (Office Action, page 4). Applicants submit that this rejection is
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`base,d on information in the German patent application that contradicts applicants' test results,
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`and request the Examiner to reconsider this rejection in view of applicants testing, the
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`Declaration, and the following comments.
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`Applicants have obtained a translation of the German patent application, which is
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`attached to the Declaration as Exhibit B. Applicants' comments in their Declaration and here are
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`

`

`Case 1:17-cv-00868-VAC-SRF Document 10-1 Filed 08/04/17 Page 5 of 9 PageID #: 183
`
`· Applicant
`Ethier
`Serial No. :
`Filed
`Page
`
`James G. Dobson, •.. and Michael F.
`
`Attorney's Dockel
`
`.0.: 07917-0450021 (UMMC 97-
`32)
`
`,
`09/672,348
`September 28, 2000
`4
`.
`
`based on this translation. As the Examiner has noted, the German patent application describes
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`the use of adenosine for increasing cell proliferation in human skin (see, e.g., the title and claim
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`1). However, applicants' claims require no increase in dermal cell proliferation, because such
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`excess cell proliferation can cause scarring, discoloration, and a variety of other skin anomalies
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`associated with hyperplasia. See, Declaration at paragraph 2.
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`Furthermore, applicants' testing, as described above, has shown that low concentrations
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`of adenosine do not increase dermal cell proliferation. Thus, when the German patent
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`application states that concentrations of adenosine as low as 0.001 % can be used for increasing
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`cell proliferation, the German patent application must be mistaken in that adenosine was not
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`likely actually administered at this low concentrati,on. There is. one paragraph in the German
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`patent application that recites the 0.0,01 % number, and this is in an extremely broad range from
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`0.001 to 10% by weight of a cosmetic composition (at page 9, 4th full paragraph). Other
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`sections of the German patent application recite higher concentrations for a lower limit of
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`adenosine. For example, the claims, recite 0.01 to 10%, with a preferred concentration of 0.1 to
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`6%. More importantly, each of the six Examples at pages 9 to 12 in the translation lists a
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`relatively high concentration of 0.1 % adenosine. See also the Declaration at paragraph 5.
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`Thus, based on applicants' test results, applicants submit that the extremely ~road range
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`of adenosine concentrations listed in the German patent application is not supported by reality.
`~-rhe low end of this unsupported range is 0.001 %; which corresponds to 3.8 x 10-5 M adenosine.
`\ This is between the 10-4 M and 10-5 M concentrations recited in the claims of the present
`'-'
`application. However, the presently claimed invention is based on the demonstration that the
`
`)
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`recited concentrations of adenosine do not increase cell proliferation. This is the exact opposite
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`of the assertions in the German patent application. It is for these reasons that the German patent
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`application recitation of adenosine concentrations less than 10-4 M (0.00265%) cannot be valid,
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`and thus the German patent application does not disclose the same invention as the proposed
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`claims in the present application. See Declaration, paragraph 5.
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`In addition, applicants submit that the dependent claims 74 to 76, and 78 are also not
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`anticipated for the same reasons discussed above for independent claim 70. Thus, applicants
`
`

`

`Case 1:17-cv-00868-VAC-SRF Document 10-1 Filed 08/04/17 Page 6 of 9 PageID #: 184
`
`ApIDlicant :
`Ethier
`Serial No. :
`Filed
`Page
`
`James G. Dobson, J •• and Michael F.
`
`Attorney's Docket. ,J.: 07917-0450021 (UMMC 97-
`32)
`
`09/672,348
`September 28, 2000
`5
`'
`
`respectfully request that the Ex~ip.er reconsider and withdraw the rejection of the claims in
`
`view of the German patent application.
`
`Next, claims 70 and 76 have been rejected as being allegedly anticipated by Hartzshtark
`
`et al. (Experentia, 1985). Applicants disagree for the following reasons.
`
`According to the Office Action, Hartzshtark discloses that the application of adenosine
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`along with isoproterenol bitartarate, terbutaline sulfate, papavarine etc., reduced the degree of
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`skin indentation, which is an indication ofa firmer and younger skin (Office Action, page 4).
`
`The Examiner concedes that Hartzshtark does not discuss whether the addition of adenosine
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`(ncreases or decreases cell proliferation, but states, "[a]bsent showing evidence on the contrary, it
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`is the position of the examiner that adenosine treatment of Hartzshtark et aI, does not increase the
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`stimulation of dermal cell proliferation and therefore, Hartzshtark et al. anticipates the instant
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`method" (Office Action, pages 4-5).
`
`As discussed above, applicants have demonstrated that certain low concentrations of
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`adenosine do not increase cell proliferation. In the enclosed Declaration, applicants describe
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`their review of the two main prior art references, and the testing they have done that supports the
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`present claims.
`
`Hartzshtark states that certain concentrations of various agents, including adenosine,
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`increase skin cyclic-AMP content and thus cause a decrease in skin indentation. Specifically,
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`Hartzshtark indicates in the Table on page 379 that the adenosine concentration effective to
`reduce indentation was 0.1 % (3.8 x 10-3 M), but also notes that they tested adenosine "at one-
`•
`third of the concentrations shown in the table [e.g., about 1.27 x 10-3 M], and at this level
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`[adenosine was] ineffective" (bottom of page 378 to top of page 379). Applicants discuss these
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`results of Hartzshtark in their Declaration, at paragraph 4.
`
`The proposed amended claims would recite a maximum concentration of adenosine of
`10-4 M. The results in Hartzshtark indicate that a concentration of adenosine of 10-4 M or lower
`would be even less effective than one-third of 0.1 % (1.27 x 10-3 M), which was ineffective in
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`their testing. See Declaration, paragraph 4., Thus, Hartzshtark does not anticipate claim 70 as
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`amended, and does not anticipate dependent claim 76, which depends from claim 70.
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`

`

`Case 1:17-cv-00868-VAC-SRF Document 10-1 Filed 08/04/17 Page 7 of 9 PageID #: 185
`
`Applicant :
`Ethier
`Serial No. :
`Filed
`Page
`
`James G. Dobs~m, ... and Michael F.
`
`Attorney's Docket. J.: 07917-045002/ (UMMC 97·
`32)
`
`09/672,348
`September 28, 2000
`6
`.
`
`35 U.S.C § 1'03
`Claims 70 and 72 to 78 have been rejected as allegedly obvious over the combination of
`
`the German patent application and Hartzshtark. Applicants traverse this rejection for the reasons
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`stated above and as follows.
`
`The Office Action states that "[n]either reference discloses the exact amounts of
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`adenosine," but concludes that "it would have been obvious for a skilled artisan at the time of the
`
`instant invention to optimize the amounts of adenosine such that the cAMP levels of skin
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`increase and thus contribute for the reduced skin indentation and hence a firmer skin" (Office
`
`Action, page 5).
`
`As discussed above, Hartzshtark indicates that adenosine was effective at a concentration
`of 0.1 %, which is 3.8 x 10-3 M. However, when they tested adenosine at a lower concentration,
`at one-third of 0.1 %, there was no effect. Thus, applicants submit that one skilled in this field
`
`would not have "optimized" the concentrations described in Hartzshtark to lower them even
`
`further. Thus, there would have been no suggestion or motivation in any of the cited references
`for one of skill in this field to us~ a maximum concentration of 10-4 M adenosine as recited in
`applicants' claim 70. Thus, claim 70, and dependent claims 72 to 78, are not obviollS in view of
`
`the cited prior art.
`
`Claim 71 has been rejected as being allegedly unpatentable over a combination of the
`German patent application of DE 1955107 and Hartzshtark in view of Brown, U.S. Patent No.
`
`5,618,544 ("Brown"). Similarly, claims 78 and 79 have been rejected as obvious over the
`
`combination of the German patent application and Hartzshtark in view of Porter, U.S. Patent No.
`
`5,785,978 ("Porter").
`Claims 71, 78, and 79 depend from claim 70, which is patentable for all the reasons
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`discussed above. Thus, these dependent claims are also patentable. However, applicants note
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`further that Brown's suggestion to apply epidermal and fibroblast growth factors to the skin
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`would not lead one of skill in the art to avoid an increase in cell proliferation, as recited in
`
`applicants' claims, because these growth factors are known to increase cell proliferation (Brown'
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`notes that these factors increase "the rate of cellular replication," at column 3, lines 25-26).
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`Thus, applicants see no suggestion or motivation to combine Brown with any of the other cited
`
`

`

`Case 1:17-cv-00868-VAC-SRF Document 10-1 Filed 08/04/17 Page 8 of 9 PageID #: 186
`
`N;~licant :
`Ethier
`Serial No. :
`Filed
`Page
`
`James O. Dobson, J •• and Michael F.
`
`Attorney's Docket
`
`.J.: 07917-0450021 (UMMC 97·
`32)
`
`091672,348
`September 28, 2000
`7
`
`references, and even if such a combination were made, one would not have achieved the claimed
`
`invention.
`As for Porter, if one of skill.in the art were to use the trans dermal patch that this patent
`
`describes, the dosage of adenosine would, according to the cited prior art, cause an increase in
`
`. skin cell proliferation andlor provide a higher concentration of adenosine than 'recited in
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`applicants' claims. Thus, applicants submit that even if Porter were combined with the German
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`o '
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`•
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`patent application or Hartzshtark, the result would not be the presently churned invention.
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`CONCLUSION
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`Attached is a marked-up version of the changes being made by the current amendment.
`
`Applicants request that the proposed claim amendment be entered and that all pending
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`claims then be allowed. No excess claims fee is required. Applicantsenclose a $55.00 check
`
`and a Petition for Extension of Time. Please apply any other charges or credits to Deposit
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`Account No. 06-1050; referencing Attorney Docket No. 07917-045002.
`
`Respectfully submitted,
`
`er Fasse
`1.
`Reg. No. 32,983
`
`Date: ___ /)_:2._-_I/_-_tJ_Z-___ _
`
`Fish & Richardson P.C.
`225 Franklin Street
`Boston, Massachusetts 02110-2804
`Telephone: (617) 542-5070
`Facsimile: (617) 542-8906
`
`70021823.doc
`
`c,
`
`

`

`Case 1:17-cv-00868-VAC-SRF Document 10-1 Filed 08/04/17 Page 9 of 9 PageID #: 187
`
`Ap';'>licant
`Ethier
`Serial No. :
`Filed
`'
`Page
`
`James O. Dobson, J •• and Michael F.
`
`Attorney's Docket .. J.: 07917-0450021 (UMMC 97-
`32)
`
`09/672,348
`September 28, 2000
`8
`.
`
`Version with Markin2;s to Show Chan2;es Made
`
`In the claims:
`
`Claims 54 to 69 have been cancelled as directed to a non-elected invention.
`
`Claim 70 has been amended as follows.
`
`70. (Amended) A method for enhancing the condition of unbroken skin of a mammal by
`
`~educing one or more of wrinkling, roughness, dryness, or laxity of the skin, without increasing
`
`dermal cell proliferation, the method comprising topically applying to the skin a composition
`
`comprising a concentration of adenosine in an amount effective to enhance the condition of the
`
`skin without increasing dermal cell proliferation, wherein the adenosine concentration applied to
`the dermal cells is 10-4 M to 10-7 M.
`
`