DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Restriction/Election
Applicant's election with traverse of the species election in the reply filed on June 8th, 2026 is acknowledged. The traversal is on the ground that the species of Species I represent two distinct types of sequences (one is a nucleic acid sequence and another is an amino acid sequence of human collagen type VII). The examiner agrees with applicant and has withdrawn the requirement for a species election. Group I (Claims 16-23) was elected; there was no argument traversing the overall restriction.
The requirement is still deemed proper and is therefore made FINAL.
In the restriction election, applicant mentioned that some articles did not look readable when submitted into PAIR. The examiner is able to read the articles submitted with the IDS documents. If applicants do not like the appearance of the references submitted, those articles need to be resubmitted into PAIR so that the clearer versions are part of the patent application record.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 16-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention. The claims recite that any cell from a blister of a patient with dystrophic epidermolysis bullosa can be genetically modified and administered to a patient for treatment of dystrophic epidermolysis bullosa. However, applicants’ specification discusses that a selection process is used and the administered cells are a population of cells enriched for mesenchymal stem cells. The specification does not identify additional cell types from the blister/blisters that can successfully generate collagen VII.
Furthermore, claim 18 recites that the, “COL7A1 gene comprises a nucleic acid sequence having 90% or more sequence identify with the nucleic acid sequence of SEQ ID: NO 1; or a nucleic acid sequence that encodes amino acid sequence having 90% or more sequence identity with amnion acid sequence of SEQ ID: NO: 2.” The specification just discloses SEQ ID:1 and SEQ ID: 2 without disclosing additional species having 90% structure in common with either SEQ ID:1 or SEQ ID:2. Thus, one cannot determine the structure of the genus.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
A described in MPEP § 2163, “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice...reduction to drawings...or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus”...See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."
One genus is a cell derived from a blister of a patient that has been genetically modified to produce Type VII collagen. In analyzing whether the written description requirement is met for the genus, the specification if first assessed to determine whether a representative number of species of the genus have been described so that one is able to comprehend the structure of the genus.
In this case, applicants’ specification (Pages 10-12) states that blister fluid containing cells is harvested from blisters of patients with dystrophic epidermolysis bullosa. The cells that are collected from the blister fluid subsequently undergo a selection process which selects for mesenchymal stem cells as discussed in pages 41-42 of the specification. These cells have markers present which indicate that they are mesenchymal stem cells (Pages 41-42 of the specification). These cells are subsequently genetically modified and can produce collagen VII. The specification only identifies selected mesenchymal stem cells derived from the blister fluid as being able to produce collage VII (Pages 10-12, 41-42, and Examples 1-2). It is unclear if other distinct types of cells derived from blister fluid are able to produce collagen VII.
An additional genus is a COL7A1 gene that comprises a nucleic acid sequence having 90% or more sequence identify with the nucleic acid SEQ ID: 1, or a nucleic acid sequence that encodes an amino acid sequence having 90% or more sequence identity with amino acid sequence SEQ ID NO:2.
Applicants’ specification states that the sequence of a COL7A1 gene such as SEQ ID:1 is not limited to any specific sequence as long as it encodes a functional collagen (Page 15, line 21-24 of the specification). The reference fails to provide examples of sequences that can successfully provide a functional collagen besides SEQ ID:1. Furthermore, the specification only provides one amino acid sequence for Collagen VII (SEQ ID:2); there is no other variations provided which would be within 90% of SEQ ID:2.
The claims do not recite limitations that state where such substitutions in the sequences can occur; therefore, any substitution of any nucleic acid or amino acid is possible. There is no indication what portion of the sequence or amino acid must be conserved and what portion can vary. Since a representative number of species for both SEQ ID:1 and SEQ ID:2 are not disclosed and the necessary sequence/amino acid portions required are unknown, one cannot determine the structure of the genus which has a 90% sequence identity to either SEQ ID:1 or SEQ ID:2 because the required sequence/amino acid portions are unknown and cannot be ascertained.
In Conclusion: Applicant is not entitled to claims which recite that any cell derived from a blister can be genetically engineered to produce collagen. Applicants teach that the blister cells undergo a selection process that selects for mesenchymal stem cells. Applicants specification only supports genetically engineering mesenchymal stem cells derived from patient skin blisters/blister fluid. Furthermore, species that represent a nucleic acid sequence having 90% or more sequence identify with nucleic acid sequence of SEQ ID: NO1 or a nucleic acid sequence that encodes an amino acid sequence having 90% or more sequence identify with the amino sequence of SEQ ID No: 2 have not been clearly and/or sufficiently described by other relevant characteristics, specified features, and/or functional attributes. Only SEQ ID: 1 and SEQ ID:2 are provide. Because only SEQ ID:1 and SEQ ID:2 are provided and given that specific identifying features/characteristics of the species of each genus were not provided, the written description requirement disclosing the complete structure of each genus for SEQ ID:1 and SEQ ID:2 is not met.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification, and are not conventional in the art as of Applicants’ effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the claimed invention in a detailed drawing, or by describing the invention with sufficient, relevant, identifying characteristics (as it relates to the claimed invention as a whole), such that one of skill in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641, 1646 (1998). In the instant case, the breath of the genus lacks a written description. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, there is not even identification of any particular portion of a sequence structure that must be conserved. As stated above, it is not even clear what region of the sequences are required and which are not required in the structure. The specification does not provide a complete structure of the variants that encompass either nucleic acid sequence SEQ ID:1 or amino acid sequence SEQ ID:2 and fails to provide a representative number of species for the encompassed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the recited genus.
The skilled artisan cannot envision the detailed chemical structure of all the fragments, derivatives, or variants, that are encompassed by the claims, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method. Adequate written description requires more than a mere statement that is part of the invention, and a reference to a potential method of isolating it. See Fiers v. Reveal, 25 USPQ2d 1601, 1606 (Fed Cir. 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481, 1483. In Fiddes, claims directed to mammalian FGFs were found to be unpatentable due to lack of written description for that broad class. The specification only provided the bovine sequence.
Enablement Rejection
Claims 16-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating dystrophic epidermolysis bullosa comprising the step of administering intradermally to a patient with dystrophic epidermolysis bullosa mesenchymal stem cells derived from a blister of the patient wherein the mesenchymal stem cells are genetically modified to produce type VII collagen, does not reasonably provide enablement for a method of treating dystrophic epidermolysis bullosa, comprising the step of administering to a patient with dystrophic epidermolysis bullosa a cell derived form a blister of the patient, wherein the cell is genetically modified to produce type VII collagen. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc. 8 USPQD2d 1217 (Fed. Cir. 1988). Whether undue experimentation is required is a conclusion reached by weighing several factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQQ2d 1400 (Fed. Cir. 1988).
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experiment to make and use the invention based on the content of the disclosure is undue.
Nature of the Invention: The invention encompasses administering to a patient a cell from a blister of a patient that has been genetically modified to produce type VII collagen.
Breadth of the Claims: The clams do not specify a particular cell type that must be used; therefore, the claims encompass any cell that can be harvested from a blister of a patient with dystrophic epidermolysis bullosa. The claims are so broad that they also include any method of administration.
Teachings from the Prior Art:
Wenzel et al. “Genetically corrected iPSCs as cell therapy for recessive dystrophic epidermolysis bullosa” Science Translational Medicine.org 26 November, 2014, Vol 6, Issue 264 teaches that IPSCs was developed from type VII collagen mutant murine fibroblast cells that developed skin fragility and blistering resembling recessive dystrophic epidermolysis bullosa (Abstract and Page 2, Results Section of Wenzel). These IPSCs could be differentiated into functional fibroblast cells that re-expressed and secreted type VII collagen and these fibroblast cells could be intradermally administered to mice (Abstract and Page 2, Figure 1). Page 6/Figure 4 description illustrates that epidermolysis improved upon administration of the fibroblast cells. The reference is acknowledging that intradermal administration was successful. Wenzel administered a cell (fibroblast cell) that is known to produce collagen VII.
Kikuchi “Gene-Modified Blister Fluid—Derived Mesenchymal Stromal Cells for Treating Recessive Dystrophic Epidermolysis Bullosa” Journal of Investigative Dermatology (2023), 143, 2447-2455 states cells can be harvested from blister fluid and passaged for several days (Page 2448, Collection and culture of MSCs from blister fluid of patients with RDEB). These passaged cells express mesenchymal stem cell markers (Page 2448, Collection and culture of MSCs from blister fluid of patients with RDEB). Figure 1C shows that these cells express CD73, CD105, and CD90 which are mesenchymal stem cell markers. After passaging the cells initially harvested from blister fluid, an additional cell population distinct from the mesenchymal cells is not shown to be present. Therefore, Kikuchi acknowledges that one cell population is present. These cells were then genetically engineered to express collagen VII (Page 2448 results section). These cells were then administered into an animal using intradermal or intrablister methods of administration to treat Dystrophic Epidermolysis Bullosa (Page 2448 Results Section).
Applicants Specification/Guidance/Working Examples:
The specification discloses that the cells are derived from blisters (Page 10 of applicants’ specification). Pages 14-15 of applicants’ specification do not clear specify what the cell is. For example Page 14, line 24 states, “The DEB patient blister derived cell may be any cell as long as it produces type VII collagen in the vicinity of the epidermal basement membrane.” Example 1 “Collection of blister derived cells” (a working example) teaches that cells are harvested from blister fluid. The cells are then placed in a medium with mesenchymal stem cell growth medium in a six well plate coated with collagen to obtain adherent cells. Then the cells are passaged in adherent culture multiple times. Page 42 of the specification discusses the FACs analysis of the blister derived cells after adherence culture. After this adherence culture phase, the blister derived cells that are exposed to the mesenchymal selection process of Example 1 are CD73,CD105, and CD90 positive (Figure 2). It is well known in the art that CD73, CD105, and CD90 are positive markers for mesenchymal stem cells. The presence of other cell types is not disclosed.
Page 30 of applicants specification states that the composition is administered to an affected area of a patient with dystrophic epidermolysis bullosa. The composition can be administered “systemically or topically” (Page 30 of applicants’ specification). The composition can also be “administered intradermally at the site of the blister or administered into a blister” (Page 30 of applicants’ specification). However, page 52 of applicants’ specification provides working examples of intradermal injection and intrablister injection. The first paragraph of page 52 of applicants specification even states, “…..it was found that intrablister injection of COL7A1 gene-introduced cells resulted in better deposition of type VII collagen in the skin than intradermal injection. It was also found that more type VII collagen could be deposited around the basement membrane when blister derived cells were used.” The specification does not clearly explain how other methods of administration mentioned on page 30 such as systemic or topical administration would be able to successfully treat epidermolysis bullosa.
Conclusion:
Applicants specification teaches that the cells are harvested directly from a blister, placed in an adherent culture in mesenchymal stem cell medium which selects for mesenchymal stem cells, and the resulting mesenchymal stem cells are then genetically modified to produce Collagen VII. This is what is enabled based on the prior art and the teachings of the specification. Furthermore, the claimed invention is only enabled for intradermal and intrablister administration of genetically altered mesenchymal stem cells.
Conclusion
All claims stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN K VAN BUREN whose telephone number is (571)270-1025. The examiner can normally be reached M-F:9:30am-5:40pm; 9:00-10:00pm.
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LAUREN K. VAN BUREN
Examiner
Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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