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 .
Response to Amendment
The amendment filed 7/11/2025, amending claims 17, 19, 23-25, 27, 36, and cancelling claims 18 and 26 is acknowledged. Claims 17,19-21,23-25,27-33 and 36-40 are pending and under examination. Applicant’s amendments to the claims have overcome each and every 112(a) and 112(b) rejection previously set forth in the Non-Final Office Action mailed 3/14/2025.
Additionally, the Applicant provided a certified English translation for JP2019-007201, which the instant application claims priority to. Therefore, the claims are entitled to the priority date of JP2019-007201, filed 1/18/2019. The rejection of claims 24-27 under 35 U.S.C. 102(a)(2) as being anticipated by Hansson has been withdrawn, as the effective filing date of the instant case is now prior to Hansson’s.
Response to Arguments
Applicant's arguments filed 7/11/2025 have been fully considered but they are not persuasive.
The Applicant notes that as Kawachi uses an HVE-J vector to introduce a type VII collagen gene to keratinocytes in vivo, while in the instant case, the cells themselves are administered to the subject, the mechanism of action is different between Kawachi and the instant case. Further, the Applicant argues that a person skilled in the art in view of Kawachi would have recognized that intrablister administration of a vector comprising type VII collagen gene alone is not sufficient, and additional components for targeting basal keratinocytes are necessary.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Kawachi was relied upon to teach intrablister administration, not how a type VII collagen gene is introduced (i.e., via cells vs. via vector), which Lundberg is relied upon to teach. Therefore, the Applicant’s arguments are not persuasive.
Additionally, the Applicant argues there would not have been a reasonable expectation of success to simply change Lundberg's route of administration, given that Kawachi's delivery mechanism using an entirely different modality - a non-viral vector comprising a targeting component in a viral envelope, vs. cells, and given the multiple components of Kawachi’s HVJ-E, there would be no motivation to modify Lundberg with the teachings of Kawachi.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as discussed in further detail in the 103 rejection below, cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious. Additionally, the Applicant fails to distinctly point out and provide evidence as to why an artisan would not have a reasonable degree of success to combine the teachings of Lundberg and Kawachi. It is unclear how “the multiple components in Kawachi’s HVJ-E” means there would be no motivation to modify Lundberg with the teaching of intrablister administration by Kawachi.
In response to applicant's argument that the claimed methods result in the unexpected benefit of sustained gene expression not taught by Kawachi, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Again, the claimed invention was rejected in view of the teachings of Lundberg and Kawachi combined, not Kawachi alone. Therefore, the Applicant’s argument are not convincing.
Priority
The claims of the instant case are entitled to the priority date of JP2019-007201, filed 1/18/2019.
Claim Rejections - 35 USC § 103 – Maintained, updated for amendments
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 17, 20, 21, 23-25, 28-33, and 36-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lundberg (WO2018154413A1, published August 30, 2018) and in further view of Kawachi (Kawachi, Masako et al. “Development of tissue-targeting hemagglutinating virus of Japan envelope vector for successful delivery of therapeutic gene to mouse skin.” Human gene therapy vol. 18,10 (2007): 881-94.).
Regarding claim 17, Lundberg teaches a method of treating dystrophic epidermolysis bullosa, comprising the steps of: (a) obtaining mesenchymal stem cells from a patient with dystrophic epidermolysis bullosa; (b) genetically modifying the cells to produce type VII collagen (i.e., restoring COL7A1 protein activity); and (c) administering (i.e., implanting) the cells of (b) to the patient (para 00022; para 00025; para 00031; para 000443) (the examiner notes that Lundberg discloses differentiating the edited MSCs into keratinocytes or fibroblasts and implanting the keratinocytes or fibroblasts into the patient, which still reads on the claim language, as MSCs were obtained and genetically modified before being administered to the patient), wherein genetically modifying the cells of (b) includes delivering a COL7A1 gene to the cells (para 00024 – wherein the one or more exons and/or introns comprise the corrected COL7A1 gene sequence; claim 64).
Further, regarding claims 24-25, Lundberg teaches method of treating dystrophic epidermolysis bullosa, comprising: administering a therapeutically-effective amount of cells which produce type VII collagen (genetically modified cells- claim 25 (para 000387; para 000443); delivering a COL7A1 gene, which encodes type VII collagen- (para 00022) to a patient in need thereof (para 00022; para 00025; para 00031; para 000443).
Additionally, regarding claim 36, Lundberg teaches a method of treating dystrophic epidermolysis bullosa, comprising: administering a therapeutically-effective amount of cells which produce type VII collagen to a patient in need thereof, the cells being mesenchymal stem cells having been previously obtained from the patient [00286; 000229] and genetically modified to produce type VII collagen (see other citations above).
Lundberg does not teach administering the cells of (b) into a blister of the patient. Lundberg does teach cells being administered to a patient via intraepidermal injection (i.e., to the epidermis) and by intradermal injection (into the skin) (para 000381).
Kawachi teaches injecting a chimeric tissue-targeting hemagglutinating virus of Japan envelope virus into a skin blister of a mouse model (claim 37- blister formed on skin of patient) of epidermolysis bullosa (Abstract). The vector introduced type VII collagen expression into the mice, resulting in efficient amelioration of the genetic defect (Abstract; pg. 887, “Efficient therapeutic gene expression in blistering mouse skin with chimeric HVJ envelope vector”). Additionally, Kawachi teaches artificially forming a blister on the skin of the patient (claim 38). “Artificial” means something made my humans, or is not natural. Therefore, Kawachi’s teaching of generating type VII collagen knockout mice via experimentation reads on “artificial” (pg. 882, “Animal”).
It would have been obvious before the effective filing date of the current invention to substitute the injecting directly into the blister as taught by Kawachi for the intradermal or intraepidermal injections taught by Lundberg. One would have a reasonable expectation for success because it is routine in the art to change the route of administration depending on the tissue/organ being targeted, and would fall under routine experimentation to perform different types of injections (i.e., intrablister vs intradermal).
Further, the focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Regarding claim 20, Lundberg teaches the mesenchymal stem cells being bone marrow- derived mesenchymal stem cells (para 0025).
Regarding claims 21 and 32, Lundberg teaches editing CD34+ cells from the patient followed by implanting the edited CD34+ cells into the patient (claim 15; clam 19). Lundberg also teaches that the CD34+ cells may be mesenchymal stem cells [000304]. Absent evidence to the contrary, Lundberg therefore teaches mesenchymal stem cells being the most abundant cells in the population administered to the patient.
Regarding claims 23, 33 and 39, Kawachi teaches the intrablister (i.e., absent evidence to the contrary, intrablister is interpreted to read on injecting into a blister, as such recited in claim 17; see [0042] of specification for reference) injection referring to an injection into the space formed between the basement membrane (i.e., basal layer) and the dermis of the patient’s skin, at a place where the basement membrane is detached from the dermis (i.e., on pg. 887, “Infectivity of chimeric HVJ in organ culture system”, Kawachi teaches that blisters of epidermolysis bullosa (EB) form due to dermo-epidermal separation- therefore, when reciting injecting into a blister, this reads on injecting into the dermo-epidermal separation space).
Regarding claim 28, Lundberg teaches the method of claim 24, wherein the cells have been obtained from the patient with dystrophic epidermolysis bullosa (para 00025; para 00031).
Regarding claim 29, Lundberg teaches the method of claim 24, wherein the cells have been obtained from bone marrow (para 00025).
Regarding claims 30 and 31, Lundberg teaches the method of claim 24, wherein the cells are mesenchymal stem cells, specifically wherein the mesenchymal stem cells are bone marrow- derived mesenchymal stem cells (claim 31) (para 00025).
Regarding claim 35, Lundberg discloses a method of preparing cells for administration to a patient in need of treatment of dystrophic epidermolysis bullosa, comprising: genetically modifying mesenchymal stem cells to produce type VII collagen, the cells having been obtained from the patient in need of treatment of dystrophic epidermolysis bullosa, wherein the genetically modified cells are capable of being administered to the patient (para 00022; para 00025; para 00031).
Regarding claim 40, Lundberg teaches the administered cells being keratinocytes or skin fibroblasts that were previously mesenchymal stem cells (claim 8, 22).
Claim(s) 19 and 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lundberg and Kawachi as applied to claims 17, 18, 20, 21, 23-26, 28-33, and 36-40 above, and further in view of Krishnan (WO2017176336A1, published October 12th, 2017).
Lundberg and Kawachi teach the claim limitations discussed above.
Regarding claims 19 and 27, Lundberg nor Kawachi teach the COL7A1 gene comprises a nucleic acid sequence having 90% or more sequence identity with the nucleic acid sequence of SEQ ID NO: 1, or a nucleic acid sequence that encodes an amino acid sequence having 90% or more sequence identity with the amino acid sequence of SEQ ID NO: 2. SEQ ID NO: 2 of the instant case corresponds to the human COL7A1 gene and is well known in the art. For example, Krishnan teaches SEQ ID NOs: 14, 18, 22, and 26 share 100% identity with SEQ ID NO: 2 of the instant case (paras 0076 and 0077). Further, SEQ ID NOs: 16, 20, 24, 26, and 28 of Krishnan share 99.9% identity with SEQ ID NO: 2 of the instant case (para 0076 and 0077). It would have been obvious to one of ordinary skill in the art before the effective filing date of the current invention to substitute the COL7A1 gene sequence taught by Krishnan for the COL7A1 gene taught by Lundberg. An artisan would have a reasonable expectation of success because SEQ ID NOs: 1 and 2 of the instant case are well-known in the art and represent the human COL7A1 gene. One of ordinary skill would be motivated to make this substitution because they hope to express the human COL7A1 gene. Further, replacing one sequence with another has long been done in the molecular biology art and would be routine.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638