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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`L’OREAL USA, INC.
`Petitioner
`
`v.
`
`UNIVERSITY OF MASSACHUSETTS
`Patent Owner
`
`
`
`
`IPR2018-00778
`Patent No. 6,423,327
`
`
`
`
`PATENT OWNER PRELIMINARY RESPONSE
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`
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`
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`

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`
`
`
`I.
`
`II.
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`B.
`
`OVERVIEW OF THE ’327 PATENT ............................................................ 3
`A.
`The Relevant Distinction Between the Epidermal vs. Dermal
`Layers of the Skin as Taught in the ’327 Patent ................................... 3
`The ’327 Patent’s Inventions Enhance the Condition of
`Unbroken, Non-Diseased Skin, Without Increasing Dermal Cell
`Proliferation ........................................................................................... 5
`The ’327 Patent’s Claims Require Applying Adenosine to the
`Dermal Cells Without Increasing Dermal Cell Proliferation ................ 9
`
`C.
`
`B.
`
`C.
`
`III. CLAIM CONSTRUCTION .......................................................................... 10
`“adenosine concentration applied to the dermal cells is 10-4 M
`A.
`to 10-7 M” ............................................................................................ 11
`Petitioner’s Proposed Construction Is Contrary To The Plain
`Meaning Of The Claim. ...................................................................... 12
`Petitioner’s Proposed Construction Is Contrary To The
`Specification ........................................................................................ 14
`Petitioner’s Proposed Construction Is Inconsistent With The
`Prosecution History ............................................................................. 16
`The Board Should Disregard the Petition’s § 112 Written
`Description Arguments and Deny the Petition ................................... 19
`
`D.
`
`E.
`
`IV. OVERVIEW OF PETITION GROUNDS .................................................... 22
`
`V.
`
`PETITIONER HAS FAILED TO SHOW A REASONABLE
`LIKELIHOOD THAT ANY CLAIM IS ANTICIPATED BY DE ’107 ...... 22
` Overview of DE ’107 .......................................................................... 22
`A.
`DE ’107 is Based on Increasing Cell Proliferation. ............................ 23
`B.
`
`DE ’107 Teaches Thousands of Formulations, But Does Not
`C.
`
`Teach Delivery of Adenosine to the Dermal Layer at All, Let
`Alone in the Claimed Range. .............................................................. 24
`D.
` DE ’107 Was Cited During Prosecution of the ’327 Patent. .............. 26
`DE ’107 Does Not Anticipate. ............................................................ 29
`E.
`
`
`ii
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`

`

`
`
`VI. PETITIONER HAS FAILED TO SHOW A REASONABLE
`LIKELIHOOD THAT ANY CLAIM IS OBVIOUS OVER DE ’107 ......... 34
`
`C.
`
`
`
`VII. PETITIONER HAS FAILED TO SHOW A REASONABLE
`LIKELIHOOD THAT ANY CLAIM IS OBVIOUS OVER THE
`COMBINATION OF JP ’153 AND DE ’107 ............................................... 40
` Overview of JP ’153 ............................................................................ 40
`A.
`JP ’153 Does Not Teach Delivery of Adenosine to the Dermal
`B.
`
`Layer of Cells at the Claimed Range of the ’327 Patent. .................... 42
`The Petition Does Not Provide A Motivation To Combine Or
`Modify JP ’153 and/or DE ’107. ......................................................... 44
`The Combination Would Necessarily Fall Outside Claim 1 of
`the ’327 Patent. .................................................................................... 47
`
`D.
`
`
`
`VIII. PATENT OWNER ASSERTS ITS RIGHT TO A TRIAL BY JURY ......... 50
`
`IX.
`
`INSTITUTION SHOULD BE BARRED BY SOVEREIGN
`IMMUNITY .................................................................................................. 50
`
`X.
`
`
`
`
`
`
`CONCLUSION .............................................................................................. 53
`
`
`
`iii
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`

`

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`
`
`
`TABLE OF AUTHORITIES
`
`Cases
`
`A123 Sys., Inc. v. Hydro-Quebec,
`626 F.3d 1213 (Fed. Cir. 2010) ............................................................................ 52
`
`
`In re Antoine,
`559 F.2d 618 (CCPA 1977) ................................................................................. 48
`
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) .............................................................................. 38
`
`
`Atlas Powder Co. v. IRECO, Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) ............................................................................ 32
`
`
`Atofina v. Great Lakes Chemical Corp.,
`441 F.3d 991 (Fed. Cir. 2006) ................................................................. 32, 33, 34
`
`
`In re Woodruff
`
` 919 F.2d 1575 (Fed. Cir. 1990) ........................................................................... 35
`
`Continental Can Co. USA, Inc., v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) ............................................................................ 33
`
`
`Elekta Instrument v. OUR Scientific Intern.,
`214 F.3d 1302 (Fed. Cir. 2000) ............................................................................ 18
`
`
`Fed. Mar. Comm’n v. S.C. State Ports Auth.,
`535 U.S. 743 (2002) ............................................................................................. 51
`
`
`General Electric Co. v. Joiner,
`522 U.S. 136 (1997) ............................................................................................. 38
`
`
`Grain Processing Corp. v. American Maize Prods., Co.,
`840 F.2d 902 (Fed. Cir. 1988) .............................................................................. 48
`
`
`In re Bond,
`910 F.2d 831 (Fed. Cir. 1990) .............................................................................. 29
`
`iv
`
`

`

`
`
`Ineos USA, LLC v. Berry Plastics, Corp.,
`783 F.3d 865 (Fed. Cir. 2015) ....................................................................... 30, 31
`
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) ............................................................................................. 45
`
`
`Library of Congress v. Shaw,
`478 U.S. 310 (1986) ............................................................................................. 51
`
`
`Millenium Pharms., Inc. v. Sandoz, Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) ..................................................................... 33, 40
`
`
`Microsoft Corp. v. Enfish, LLC,
`662 F. App’x 981 (Fed. Cir. 2016) ...................................................................... 46
`
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) ............................................................................ 10
`
`
`Quantum Corp. v. Rodime, PLC,
`65 F.3d 1577 (Fed. Cir. 1995) .............................................................................. 20
`
`
`Regents of Univ. Of N.M. v. Knight,
`321 F.3d 1111 (Fed. Cir. 2003) ............................................................................ 52
`
`
`Richardson v. Suzuki Motor Co.,
`868 F.2d 1226 (Fed. Cir. 1989) ............................................................................ 29
`
`
`Securus Techs., Inc. v. Global Tel Link Corp.,
`701 Fed. Appx. 971 .............................................................................................. 45
`
`
`Oil States Energy Servs., LLC v. Greene’s Energy Group, LLC,
`584 U.S. __ (2018) ............................................................................................... 50
`
`
`Tegic Commc’ns Corp. v. Bd. Of Regents of Univ. of Tex. Sys.,
`458 F.3d 1355 ....................................................................................................... 52
`
`
`Transocean Offshore Deepwater Drilling, Inc. v. Maersk Contractors USA, Inc.,
`617 F.3d 1296 (Fed. Cir. 2010) ............................................................................ 45
`
`
`
`v
`
`

`

`
`
`Verdegaal Bros. v. Union Oil Co. of Cal.,
`814 F.2d 628 (Fed. Cir. 1987) .............................................................................. 29
`
`
`
`Regulations
`
`37 C.F.R. § 42.104(b)(2) .......................................................................................... 19
`
`
`
`
`vi
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`

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`
`I.
`
`INTRODUCTION
`
`Every challenged claim of U.S. Patent No. 6,423,327 (“the ’327 Patent”)
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`recites a method of enhancing the condition of skin without increasing dermal cell
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`proliferation by applying a particular concentration of the compound adenosine to
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`the dermal cells, i.e., the cells in the dermal layer of the skin which lies below the
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`epidermal layer at the surface of the skin. Each of the Petitioner’s invalidity
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`arguments depends on the Board adopting a faulty claim construction that rewrites
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`the limitation specifying a range of concentrations “applied to the dermal cells” to
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`mean instead the concentration “applied to the epidermal layer.” This is an
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`impermissible rewriting of the claim that should be rejected, and the Petition
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`should be denied on this basis alone.
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`It is readily apparent that Petitioner is seeking to impermissibly rewrite the
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`limitation rather than proposing to interpret it. Petitioner’s own expert
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`acknowledges in his declaration that the dermis and epidermis of the skin are
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`separate layers, the patent refers to them separately, and in response to a notice of
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`reasons for allowance during prosecution the applicant stated that the specified
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`concentration is not what is applied to the surface of the skin, but rather what is
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`applied to the dermal layer (through the epidermis).
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`If a proper construction (i.e., dermal means dermal) is applied, the Petition
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`fails without further examination. This is because Petitioner makes no attempt to
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`1
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`establish invalidity under the proper construction. To the contrary, Petitioner
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`claims that it is not even possible to know the adenosine concentration at the
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`dermal layer based on what is applied topically (a Section 112 argument that
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`Petitioner makes in the context of asking the Board to change “dermal” to
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`“epidermal”).
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`Petitioner is wrong, but that does not matter. Section 112 arguments are not
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`proper in an IPR. And while claim terms with multiple plausible interpretations
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`may be read to be valid, this doctrine does not allow a claim to be rewritten so that
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`it does not have its ordinary meaning.
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`The Petition makes a variety of other arguments, all of which fail even if the
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`Board were to interpret “dermal” to mean “epidermal.” For example, the primary
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`prior art reference teaches that it is essential to increase cell proliferation in order
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`to improve the condition of the skin, while the ’327 Patent teaches the opposite,
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`and the claims recite “without increasing dermal cell proliferation.” The Petition
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`nevertheless argues that it would be obvious based on this reference alone, or in
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`combination with a reference that says nothing about cell proliferation, to create a
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`formulation that does not increase cell proliferation. That is not a proper basis to
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`find anticipation or obviousness.
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`The flaws in Petitioner’s invalidity arguments are addressed below, but the
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`Patent Owner respectfully submits that the Board need not reach them. Should the
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`2
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`Board conclude that Petitioner has not established that “applied to the dermal
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`cells” actually means “applied to the epidermal layer,” the Petition can be denied
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`without more.
`
`II.
`
`OVERVIEW OF THE ’327 PATENT
`
`A. The Relevant Distinction Between the Epidermal vs. Dermal Layers
`of the Skin as Taught in the ’327 Patent
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`The ’327 Patent originated from the discovery of Dr. James Dobson and Dr.
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`Michael Ethier that adenosine could be administered in such a way as to stimulate
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`DNA synthesis, increase protein synthesis, and increase cell size in human skin
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`fibroblasts. (Ex. 1001 at 1:37-41.)
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`The patent states, “[s]kin includes a surface layer, known as the epidermis,
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`and the deeper connective tissue layer, known as the dermis. The epidermis
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`undergoes continuous turnover as the outermost cells are exfoliated and replaced
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`by cells that arise from the inner dermal layers.” (Id. at 1:19-24.) “The dermis is
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`composed of a variety of cell types, including fibroblasts.” (Id. at 1:24-25.)
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`A simple diagram of the skin is:
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`3
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`

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`The ’327 Patent seeks to address a specific problem concerning dermal
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`fibroblasts that occurs as humans age, namely “[s]kin thickness begins to decline in
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`humans after the age of 20 as the dermis becomes thinner and the number of skin
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`fibroblasts declines.” (Ex. 1001 at 1:26-34.) Furthermore, “[a]s skin ages, or is
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`exposed to UV light and other environmental insults, changes in the underlying
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`dermis can lead to the functional and morphological changes associated with
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`damaged skin. Decreases in the abundance and function of products of the
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`fibroblasts, which include [proteins] collagen and proteoglycans, are believed to
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`play major roles in wrinkled and damaged skin.” (Id.)
`
`Dr. Dobson and Dr. Ethier discovered that it is these dermal cell layer
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`fibroblasts that are the cells for which DNA synthesis, protein synthesis and cell
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`size are enhanced by the ’327 Patent’s delivery of small concentrations of
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`adenosine to the dermal layer. (Id. at 1:24-25.)
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`They also discovered that too much adenosine is counterproductive and that
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`only a low concentration should reach the dermal layer. (Id. at 2:26-35.) Thus
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`(and contrary to Petitioner’s primary reference), in the claimed invention the
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`concentration is held low to avoid cell proliferation. (Id. at 10:18-26.) In other
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`words, the inventors discovered that the proper way to address thinning of the
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`dermis is not to try to increase the number cells using higher adenosine
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`concentrations, but to enhance existing dermal cells to help them remain robust.
`
`4
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`

`

`
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`B. The ’327 Patent’s Inventions Enhance the Condition of Unbroken,
`Non-Diseased Skin, Without Increasing Dermal Cell Proliferation.
`
`In view of the above problems associated with aging skin, the ’327 Patent
`
`teaches “an invention [that] is suitable for treating skin of a mammal, e.g., a
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`human, for which promotion of fibroblast-associated dermal functions is desired.
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`For example, promotion of fibroblast functions is desirable in enhancing the
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`condition of aged skin, which is associated with a decrease in dermal cell function
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`and is characterized by increased dryness or roughness, or both.” (Ex. 1001 at
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`3:23-29.) The ’327 Patent’s “method can also be used on subjects having
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`otherwise damaged skin, e.g., wrinkled skin and skin with a non-proliferative
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`disorder. The method can [be] further used prophylactically on a subject to
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`minimize deterioration of skin condition associated with aging or environmental
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`factors, such as photodamage.” (Ex. 1001 at 3:29-35.)
`
`The ’327 Patent teaches that materially increasing dermal cell proliferation
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`is undesirable. Increasing cell proliferation would mean increasing cell number, in
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`regard to which the ’327 Patent states: “The adenosine is added so that it does not
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`cause proliferation of the dermal cell.” (Ex. 1001 at 1:59-60; see also id. at 1:66-
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`67 (“The adenosine . . . does not cause proliferation of the dermal cell.”); id. at 2:6-
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`8 (“wherein addition of the adenosine does not cause proliferation of the dermal
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`cell”); id. at 10:20-21 (“without increasing dermal cell proliferation . . .”).) During
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`prosecution, the applicant further explained that the “claims require no increase in
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`5
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`

`
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`dermal cell proliferation, because such excess cell proliferation can cause scarring,
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`discoloration, and a variety of other skin anomalies associated with hyperplasia.”
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`(Ex. 1009 at 84.)
`
`As noted above, instead of addressing a skin disorder by promoting
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`increased cell proliferation, the ’327 Patent teaches increasing cell size, protein
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`synthesis and DNA synthesis, by administering a “therapeutically effective
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`amount” of adenosine to dermal fibroblasts but without increasing dermal cell
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`proliferation. (See, e.g., Ex. 1001 at 2:1-3 (“provided in the invention is a method
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`of increasing cell size in a dermal cell in non-diseased skin of a mammal, e.g., a
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`human”); id. at 1:61-62 (“[t]he invention also features a method of increasing
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`protein synthesis in a dermal cell of non-diseased skin of a mammal”); id. at 1:54-
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`56 (“included in the invention is a method for increasing DNA synthesis in a
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`dermal cell of non-diseased skin of a mammal”); id. at 1:38-40 (“We have
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`discovered that adenosine stimulates DNA synthesis, increases protein synthesis,
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`and increases cell size . . . .”).)
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`By definition, to achieve the benefits of adenosine-induced increased dermal
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`fibroblast activity, a requisite concentration of adenosine must reach the lower
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`dermal cell layer of the skin, in accordance with Dr. Dobson’s and Dr. Ethier’s
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`invention. Thus, the ‘327 Patent teaches both the proper range to reach the dermal
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`layer and mechanisms to get it there.
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`6
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`For the proper concentration range at the dermal layer, the ’327 Patent
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`includes several ex vivo experimental results showing the effect of delivering
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`disclosed concentrations of adenosine between 10-3 M and 10-7 M, more preferably
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`10-4 M, ex vivo to dermal fibroblasts. (See, e.g., Ex. 1001 at 6:15-9:50; see also id.
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`at 3:22-6:13.)
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`For example, the ’327 Patent used a fluorescent-activated cell sorter and
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`forward light scatter to determine cell size in cultured dermal cells that were
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`exposed to specific adenosine concentrations at the dermal cells. (Ex. 1001 at
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`7:17-29.) For DNA synthesis, cultured dermal fibroblasts were exposed to, e.g.,
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`10-4 M adenosine, and supplied with [3H] (i.e., tritium-labeled, tritium being a
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`radioactive isotope of hydrogen) thymidine, whose incorporation would indicate
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`DNA synthesis activity. (Ex. 1001 at 6:55-62.) To observe the effect on protein
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`synthesis, similarly, cultured dermal fibroblasts were exposed to, e.g., 10-4 M
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`adenosine, and supplied with [3H] phenylalanine, an amino acid, which would be
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`incorporated during protein synthesis. (Ex. 1001 at 6:55-62.) Statistically
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`significant increases in DNA synthesis (see, e.g., Figure 1A) and protein synthesis
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`(Figures 2A and 2B) are included with the specification’s narrative explanation of
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`the benefits of the ’327 Patent’s invention. (Ex. 1001 at 6:15-9:50.)
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`The patent further teaches mechanisms to apply the therapeutic
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`concentration to the dermal layer in vivo through topical application to the
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`7
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`

`

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`epidermis. The ’327 Patent teaches, inter alia, that “[f]or topical application, the
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`penetration of adenosine into skin tissue may be enhanced by a variety of
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`methods….” (Ex. 1001 at 5:13-15.) “Preferably, the penetration resulting from
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`these methods is enhanced with a chemical transdermal delivery agent such as
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`dimethyl sulfoxide (DMSO) or the nonionic surfactant, n-decylmethyl sulfoxide
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`(NDMS), as described in Choi et al., Pharmaceutical Res., 7(11):1099, 1990.)”
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`(Ex. 1001 at 5:18-24.) The penetration is done to achieve the proper concentration
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`at the dermal layer, and this may not be the concentration at the surface.
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`The Petition itself recognizes the ’327 Patent’s teaching of enabling the
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`requisite concentration of adenosine to penetrate from the outer epidermal layer to
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`the lower dermal cell layer where the adenosine can interact with dermal
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`fibroblasts. (See, e.g., Paper 2 at 33.) The Petition states, inter alia, that “‘topical
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`application’ of a composition to ‘unbroken skin’ necessarily requires application of
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`the composition to the outer, epidermal layer of the skin, rather than directly to the
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`inner, dermal layer.” (Id.) Petitioner’s expert likewise admits (unsurprisingly) that
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`a lotion cannot be applied directly to the dermal layer and “a skilled artisan would
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`have understood that dermal fibroblasts are covered by the outer, epidermal layer
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`of the skin.” (Ex. 1010, ¶31.) It can only be applied through the epidermal layer.
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`The Petition goes on to argue that it is not possible to know the
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`concentration at the dermal layer based on the concentration applied topically.
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`8
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`While it is true that the concentration at the surface may not be the same as in the
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`dermal layer, Petitioner is nevertheless wrong as explained below.
`
`C. The ’327 Patent’s Claims Require Applying Adenosine to the Dermal
`Cells Without Increasing Dermal Cell Proliferation.
`
`As noted above, the ’327 Patent claims methods for enhancing the condition
`
`of unbroken mammalian skin by delivering a claimed concentration of adenosine
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`to the layer of the skin known as the “dermal” layer and without increasing cell
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`proliferation. (Ex. 1001 at 10:16-47.)
`
`Claim 1, the sole independent claim of the ’327 Patent, recites:
`
`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.
`
`
`(Ex. 1001 at 10:16-47 (emphasis added).) Although the claimed composition is
`
`topically applied to the epidermal layer, the claim explicitly requires that the
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`recited concentration range reach the dermal cell layer, stating “wherein the
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`adenosine concentration applied to the dermal cells is 10-4 M to 10-7 M.” (Ex.
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`1001 at 10:16-47) (emphasis added). As noted during prosecution (in the Petition),
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`this can correspond to a range of .00000265-.00265%. (See Ex. 1009 at 90-91.)
`
`9
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`

`

`
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`III.
`
`CLAIM CONSTRUCTION
`
`Here, Patent Owner timely filed its Unopposed Motion for District Court-
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`Type Claim Construction in Accordance with 37 C.F.R. § 42.100(b) that included
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`the requisite certification that the ’327 Patent will expire on October 26, 2018.
`
`(See Paper 6.) The Board granted the Motion on June 21, 2018. (Paper 7.)
`
`Accordingly, in this proceeding, the words of a claim should be “generally
`
`given their ordinary and customary meaning,” which is “the meaning that the term
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`would have to a person of ordinary skill in the art in question at the time of the
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`invention, i.e., as of the effective filing date of the patent application.” Phillips v.
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`AWH Corp., 415 F.3d 1303, 1312-1313 (Fed. Cir. 2005). To ascertain the ordinary
`
`and customary meaning, courts look to “those sources available to the public that
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`show what a person of skill in the art would have understood disputed claim
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`language to mean” including “the words of the claims themselves, the remainder of
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`the specification, the prosecution history, and extrinsic evidence concerning
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`relevant scientific principles, the meaning of technical terms, and the state of the
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`art.” Id. at 1314. “However, while extrinsic evidence can shed useful light on the
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`relevant art, … it is less significant than the intrinsic record in determining the
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`legally operative meaning of claim language.” Id. at 1318 (internal quotation
`
`marks omitted).
`
`
`
`10
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`

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`
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`A. “adenosine concentration applied to the dermal cells is 10-4 M to 10-7
`M”
`
`The Petition requests a construction of the phrase “the adenosine
`
`concentration applied to the dermal cells is 10-4 M to 10-7 M” as appears in Claim 1
`
`of the ’327 Patent. (See, e.g., Paper 2 at 36.) Petitioner asserts that the claim
`
`language “applied to the dermal cells” refers to the concentration of adenosine that
`
`is applied not to the dermal cells, but to the outer epidermal layer of the skin.
`
`As explained below, Petitioner’s proposed construction is contrary (and, in
`
`fact, repugnant) to the ordinary meaning of “dermal,” it is inconsistent with the
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`patent’s specification, and it is inconsistent with the statements made about the
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`meaning of the term during prosecution. For these reasons, Patent Owner
`
`respectfully requests that this language be construed to mean what it says – that the
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`recited concentration is the concentration that is applied to the dermal cells.
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`The resolution of this issue is dispositive, since the Petitioner makes no
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`effort to show or even argue that the concentration requirements are met in any
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`prior art at the dermal layer. Quite the contrary, as discussed below, the Petitioner
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`goes so far as to claim that it is impossible to know the concentration at the dermal
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`layer for the ’327 Patent and, by extension, the prior art. While not true,
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`Petitioner’s argument highlights that it has not attempted to establish invalidity if
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`the claims are directed to adenosine concentrations applied to the dermal cells.
`
`
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`11
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`
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`B. Petitioner’s Proposed Construction Is Contrary To The Plain
`Meaning Of The Claim.
`
`The Petition asserts that “the adenosine concentration applied to the dermal
`
`cells is 10-4 M to 10-7 M” should be construed to refer to “the concentration of
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`adenosine in the composition that is topically applied to the unbroken, outer
`
`epidermal layer of a region of the skin containing the dermal cells.” (Paper 2 at
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`31-32) (emphasis in original).
`
`In other words, the Petitioner’s proposal is that the claim language “applied
`
`to the dermal cells,” does not mean “applied to the dermal cells” at all, rather it
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`means “applied to the outer epidermal layer of the skin.” Petitioner’s claim
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`construction should be rejected.
`
`Petitioner’s proposed construction is directly contrary to the plain language
`
`of the claim, because the claim recites that “the adenosine concentration applied to
`
`the dermal cells is 10-4 M to 10-7 M.” (emphasis added). The language is clear.
`
`The recited concentration is the concentration that comes into contact with the
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`dermal cells, not the “unbroken epidermal layer of the skin” as Petitioner proposes.
`
`Petitioners addition of the phrase “epidermal layer of a region of the skin
`
`containing the dermal cells” confuses the proposed construction. First, there is no
`
`region of the epidermal layer that contains the dermal cells. They are called
`
`12
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`

`
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`dermal cells because they are in the dermal layer. As noted throughout the ‘327
`
`Patent (quoted above), the epidermis and dermis are separate layers.1
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`In view of this, the added “region” language actually contradicts itself. Does
`
`it mean that one must find a region of the epidermal layer that has dermal cells?
`
`That is nonsensical – the epidermal layer does not contain dermal cells; the dermal
`
`layer does. Or perhaps it means that the compound is applied at the epidermal
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`layer in an area where the skin as a whole includes dermal cells? That would be all
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`of the skin, rendering the language meaningless.
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`Petitioner’s expert is no help. Like the Petition itself, the expert does not
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`explain, support, adopt or endorse the language. Although the Petitioner’s expert’s
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`declaration includes a discussion of skin layers and variables that would
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`supposedly influence the concentration of adenosine that reaches the dermal cells,
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`
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` 1
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` Any number of extrinsic sources confirm this plain meaning of “epidermis” and
`“dermis.” For example, the American Academy of Dermatology Association has a
`tutorial describing the separate layers of skin as: “Epidermis is the top layer of the
`skin, the part of the skin you see. Dermis is the second layer of skin. It’s much
`thicker and does a lot for your body. Subcutaneous fat is the bottom layer.” The
`tutorial includes a figure showing the separate layers.
`
`
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`https://www.aad.org/public/kids/skin/the-layers-of-your-skin . Petitioners’ expert
`also acknowledges them to be separate layers. (Ex. 1010 ¶ 31.)
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`he ignores this “region of the skin containing the dermal cells” language
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`completely. (See Ex. 1010 ¶¶ 30-36.) He does not even purport to say this
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`“region” aspect of the limitation (whatever it means) would be met in the prior art.
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`In short, the language makes no sense, and the Petition as a whole shows
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`that to be the case. The Petition includes no argument in support of using this
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`phrase in the construction – no definitions, no cites to the specification or
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`prosecution history. Petitioners’ expert neither offers support nor does he opine
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`that the “region” language is met in any prior art. This provides an additional
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`ground for denying the Petition – the Petitioner does not attempt to show that the
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`full claim construction it proposes is actually present in the prior art.
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`In reality, it does not appear that the “region” language is offered as a
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`substantive limitation, but rather is an effort to obscure the fact that the proposed
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`construction rewrites “dermal layer” to “epidermal layer.” Again, the proposal is
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`repugnant to the ordinary meaning of the term “dermal.” Petitioner’s proposal to
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`construe “dermal” to mean “epidermal” is simply wrong, and it should be rejected.
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`C. Petitioner’s Proposed Construction Is Contrary To The
`Specification.
`
`The specification also contradicts Petitioner’s proposed construction. The
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`very first sentence of the specification notes the basic truth that these layers of skin
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`are separate: “Skin includes a surface layer, known as the epidermis, and a deeper
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`connective tissue layer, known as the dermis.” (Ex. 1001 at 1:20-21.)
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`Petitioner nevertheless asserts that “the only disclosure in the ’327 patent
`
`where adenosine is ‘applied to dermal cells’ is associated with ex vivo methods
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`(direct application to dermal fibroblasts in cell cultures), and not in vivo methods
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`(topical application to human skin) as required by claim 1.” (Paper 2 at 32.)
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`Petitioner’s argument about what the specification discloses is incorrect.
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`In the ’327 Patent, direct application to dermal cells ex vivo was done to
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`illustrate the effect of particular concentrations at the dermal layer, again
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`confirming that the recited range is at the dermal layer. (Ex. 1001 at 9:5-50.)
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`Accordingly, the specification explains that adenosine containing compositions are
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`“preferably applied [to the dermal cells] by topical routes to exert local therapeutic
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`effects,” and that they “may be applied directly and mechanically rubbed into the
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`skin,” or “incorporated into a transdermal patch that is applied to the skin.” (Ex.
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`1001 at 5:12-17 (emphasis supplied).) The specification goes on to explain, “the
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`penetration resulting from these methods is enhanced with a chemical transdermal
`
`delivery agent such as dimethyl sulfoxide (DMSO) or the nonionic surfactant, n-
`
`decylmethyl sulfoxide (NDMS), as described in Choi et al., Pharmaceutical Res.,
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`7(11): 1099, 1990.” (Ex. 1001 at 5:19-25.)
`
`In short, the patent identifies the proper concentration at the dermal layer
`
`and verifies it using ex vivo testing of dermal cells, and it explains that application
`
`of that concentration at the dermal layer can be achieved by applying a compound
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`topically in a way where the proper concentration of adenosine penetrates to the
`
`dermal layer.
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`Thus, not only does the specification disclose the application of adenosine to
`
`the dermal cells in vivo, it describes doing so by topical application of a
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`formulation where some penetrates into the dermal layer at the appropriate
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`concentration (as determined by ex vivo testing).
`
`
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`The specification fully supports the plain meaning of “dermal cells” as
`
`“dermal cells,” i.e. cells in the dermal layer.
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`D. Petitioner’s Proposed Construction Is Inconsistent With The
`Prosecution History.
`
`Finally, the prosecution history also supports the conclusion that “applied to
`
`the dermal cells” means “applied to the dermal cells.”
`
`With the March 18, 2002 Notice of Allowability finally allowing the claims
`
`of the ’327 Patent, the Examiner provided a statement of reasons for allowance.
`
`(See Ex. 1009 at 156-158.) In it, the Examiner characterized the claims as being
`
`directed to “a method of enhancing the condition of unbroken skin by reducing
`
`wrinkling or dryness or laxity of skin, without increasing dermal cell proliferation,
`
`where the method comprises administering adenosine at a concentration of 10-4 M
`
`to 10-7 M, to