8Notice 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 .
Status of Claims
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on June 24, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on June 8, 2026. Claims 1, and 4 – 11, and 13 - 23 are currently pending. Claims 1 and 4 have been amended, and claims 24 and 25 have been canceled in the Applicant’s amendment filed June 8, 2026. (Claims 2,3, and 12 were previously canceled).
Claims 1 and 4 are directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(b), claims 5 – 11, and 13 - 23 , directed to the process of making or using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on June 17, 2025 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Therefore, claims 1, and 4 – 11, and 13 - 23 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed 13 July, 2022, is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/013650, filed 15 January, 2021, which claims the benefit of Provisional Application 62/961,838, filed 16 January, 2020.
Therefore, the earliest priority date is 16 January, 2020.
Withdrawn Objections/Rejections
Claim Rejection - 35 USC § 112(b)
The rejection of claims 1, 4, 24, and 25 is withdrawn under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1 and 4 have been amended to no longer be indefinite.
In view of the withdrawn rejection, Applicant’s arguments are moot.
Claim Rejection - 35 USC § 103
The rejection of claims 1 and 4 is withdrawn under 35 U.S.C. 103 as being unpatentable over Sobol et al. (hereinafter referred to as “Sobol”) (US 2002/0006413 A1, published January 17, 2002) (also listed in the IDS filed August 7, 2024), and further in view of Hendrayani et al. (hereinafter referred to as “Hendrayani”) (Hendrayani SF et al. The inflammatory/cancer-related IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and maintains the active state of breast myofibroblasts. Oncotarget. 2016 Jul 5;7(27):41974-41985. doi: 10.18632/oncotarget.9633. PMID: 27248826; PMCID: PMC5173109).
Claim 1 has been amended to recite that the genetically engineered dermal fibroblasts express one or more genes that are downregulated in CAFs comprising HAPLN1 or TG2, and that silence one or more genes upregulated in cancer CAFs comprising TGFBR1 or STAT3.
In view of the withdrawn rejection, Applicant’s argument is moot.
Claim Rejection - 35 USC § 112(a) Scope of Enablement
The rejection of claims 1 and 4 is withdrawn under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
The scope of claims 1 and 4 has been amended, and thus, claims 1 and 4 are allowed.
In view of the withdrawn rejection, Applicant’s arguments are moot.
New Objections/Rejections
Claim Rejection - 35 USC § 112(a) Scope of Enablement
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 5 – 9 and 18 – 23 are newly 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 for inhibiting ECM remodeling in a microenvironment of a colorectal cancer tumor, said method comprising administering a composition comprising genetically engineered dermal fibroblasts that express one or more genes that are downregulated in CAFs comprising HAPLN1 or TG2, and that silence one or more genes upregulated in cancer CAFs comprising TGFBR1 or STAT3, wherein the method is performed in a mouse,
does not reasonably provide enablement for inhibiting ECM remodeling in a microenvironment of any cancerous tumor, genetically engineering any fibroblasts (e.g., cardiac, pulmonary, etc.) that express one or more genes that are downregulated in carcinoma-associated fibroblasts (CAFs) comprising genipin or silencing any other genes upregulated in CAFs, expressing any gene that is downregulated in carcinoma-associated fibroblasts or any gene that is upregulated in cancer CAFs, or that the method is performed in a human.
The Specification does not enable any person skill 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 claims, when given the broadest possible interpretation a composition comprising genetically engineered fibroblasts that express one or more genes that are downregulated in CAFs, and that silence one or more genes that are upregulated in cancer CAFs. 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 patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
Nature of invention. The invention encompasses a method of inhibiting CM remodeling in a microenvironment of a cancerous tumor, said method comprising administering a composition comprising genetically engineered dermal fibroblasts that express one or more genes that are downregulated in CAFs, and that silence one or more genes that are upregulated in cancer CAFs
Scope of the invention. The invention encompasses a method inhibiting progression of a cancerous tumor.
Number of working examples and guidance. In the instant case, Applicant provides two relevant working example. In Example 7, the as-Filed Specification teaches that to produce genetically engineered STAR fibroblasts, two sets of genes will be edited in the genome of the dermal fibroblasts (Paragraph [0086]). The as-Filed Specification teaches the target genes to be modified in the STAR fibroblast, wherein HAPLN1-Flag and TG2-Flag are expressed, and TGFBR1 and Stat3 are silenced (Table 1).
Further, Example 8 teaches the therapeutic efficacy of these STAR fibroblasts, wherein mice with CRC (colorectal cancer) are used to test the efficacy of STAR fibroblasts (Paragraph [0088]). The disclosure teaches that it is expected that the ECM alignment and the CAF marker expression will be reduced compared to the controls (Paragraph [0089]). There are no other examples of such fibroblasts, and no other target genes being edited that retain this therapeutic efficacy. Additionally, the ECM alignment will only be reduced in this model wherein the mice have CRC, i.e. no other cancer models have been tested.
State of the art. Although the field of fibroblasts is highly developed, field of genetically
edited fibroblasts are not highly developed. The art must therefore be considered to be poorly developed.
Unpredictability of the art. Before the effective filing date of the claimed invention, it was
known in the art that the CRISPR/Cas9 system was used to disrupt four genes in goat fetal fibroblasts, as evidenced by Ni et al. (Ni W. et al. Efficient gene knockout in goats using CRISPR/Cas9 system. PLoS One. 2014 Sep 4;9(9):e106718. doi: 10.1371/journal.pone.0106718. PMID: 25188313; PMCID: PMC4154755.) (Abstract). This prior art teaches that the CRISPR/Cas 9 system was used in a specific line of fibroblasts.
Further, it was known in the art that cell viability and growth rather vary among different fibroblast lines following transfections, as taught by Howden et al. (Howden SE. et al. Simultaneous reprogramming and gene editing of human fibroblasts. Nat Protoc. 2018 May;13(5):875-898. doi: 10.1038/nprot.2018.007. Epub 2018 Apr 5. PMID: 29622803; PMCID: PMC5997775.) (pg. 5, second paragraph). Howden et al. teaches that primary fibroblasts senesce quickly, and therefore, cells that are low in passage number should be used in transfection experiments (pg. 5, second paragraph).
Additionally, it was known in the art that Swiss 3T3 fibroblast cell lines were modified to catalytically active tTGase (tissue transglutaminase) under control of the tetracycline regulated system, as evidenced by Balklava et al. (Balklava Z. et al. Analysis of tissue transglutaminase function in the migration of Swiss 3T3 fibroblasts: the active-state conformation of the enzyme does not affect cell motility but is important for its secretion. J Biol Chem. 2002 May 10;277(19):16567-75. doi: 10.1074/jbc.M109836200. Epub 2002 Feb 26. PMID: 11867617.). This references teaches a specific fibroblast cell line that has been genetically engineered.
Amount of Experimentation Required. Given the unpredictability of the art, the poorly
developed state of the art with regard to editing various different lines of fibroblasts, and the variability in viability of the genetically modified fibroblasts, the skilled artisan would have to conduct undue, and unpredictable experimentation to practice the claimed invention using the composition comprising the genetically modified fibroblasts. Further, due to the lack of specific guidance in the specification for modifying fibroblasts other than dermal fibroblasts, it would require undue experimentation to practice the breadth of the instant methods as claimed.
Claims 10, 11, and 13 - 17 are newly 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 for inhibiting
progression of a lung cancer tumor, said method comprising administering a composition comprising genetically engineered dermal fibroblasts that express one or more genes that are downregulated in CAFs comprising HAPLN1 or TG2, and that silence one or more genes upregulated in cancer CAFs comprising TGFBR1 or STAT3, wherein the method is performed in a human ex vivo,
does not reasonably provide enablement for inhibiting ECM remodeling in a microenvironment of any cancerous tumor, genetically engineering any fibroblasts (e.g., cardiac, pulmonary, etc.) that express one or more genes that are downregulated in carcinoma-associated fibroblasts (CAFs) comprising genipin or silencing any other genes upregulated in CAFs, expressing any gene that is downregulated in carcinoma-associated fibroblasts or any gene that is upregulated in cancer CAFs, or that the method is performed in a human in vivo.
The Specification does not enable any person skill 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 claims, when given the broadest possible interpretation a composition comprising genetically engineered fibroblasts that express one or more genes that are downregulated in CAFs, and that silence one or more genes that are upregulated in cancer CAFs. 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 patent coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is not based on a single factor but is rather a conclusion reached by weighing many factors (See Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter, 1986) and In re Wands, 8USPQ2d 1400 (Fed. Cir. 1988); these factors include the following:
Nature of invention. The invention encompasses a method of inhibiting progression of a cancer tumor, said method comprising administering a composition comprising genetically engineered dermal fibroblasts that express one or more genes that are downregulated in CAFs, and that silence one or more genes that are upregulated in cancer CAFs
Scope of the invention. The invention encompasses a method inhibiting progression of a cancerous tumor.
Number of working examples and guidance. In the instant case, Applicant provides two relevant working examples. In Example 7, the as-Filed Specification teaches that to produce genetically engineered STAR fibroblasts, two sets of genes will be edited in the genome of the dermal fibroblasts (Paragraph [0086]). The as-Filed Specification teaches the target genes to be modified in the STAR fibroblast, wherein HAPLN1-Flag and TG2-Flag are expressed, and TGFBR1 and Stat3 are silenced (Table 1).
Further, Example 9 teaches the prototype STAR fibroblasts can suppress tumor growth, cancer cell invasion, and the development of drug resistance in cancer cells in a 3D culture model (Paragraph [0091]). Example 9 teaches a tumor spheroid consisting of human lung cancer cells (A549) were embedded in a 3D collagen matrix and co-cultured with prototype STAR fibroblasts (Paragraph [0093]). The prototype STAR fibroblasts suppressed cancer invasion by approximately 40% (Paragraph [0093]).
There are no other examples of such fibroblasts, and no other target genes being edited that retain this therapeutic efficacy. Additionally, the ECM alignment will only be reduced in this 3D culture model using human lung cancer cells, i.e. no other models have been tested.
State of the art. Although the field of fibroblasts is highly developed, field of genetically
edited fibroblasts are not highly developed. The art must therefore be considered to be poorly developed.
Unpredictability of the art. Before the effective filing date of the claimed invention, it was
known in the art that the CRISPR/Cas9 system was used to disrupt four genes in goat fetal fibroblasts, as evidenced by Ni et al. (Ni W. et al. Efficient gene knockout in goats using CRISPR/Cas9 system. PLoS One. 2014 Sep 4;9(9):e106718. doi: 10.1371/journal.pone.0106718. PMID: 25188313; PMCID: PMC4154755.) (Abstract). This prior art teaches that the CRISPR/Cas 9 system was used in a specific line of fibroblasts.
Further, it was known in the art that cell viability and growth rather vary among different fibroblast lines following transfections, as taught by Howden et al. (Howden SE. et al. Simultaneous reprogramming and gene editing of human fibroblasts. Nat Protoc. 2018 May;13(5):875-898. doi: 10.1038/nprot.2018.007. Epub 2018 Apr 5. PMID: 29622803; PMCID: PMC5997775.) (pg. 5, second paragraph). Howden et al. teaches that primary fibroblasts senesce quickly, and therefore, cells that are low in passage number should be used in transfection experiments (pg. 5, second paragraph).
Additionally, it was known in the art that Swiss 3T3 fibroblast cell lines were modified to catalytically active tTGase (tissue transglutaminase) under control of the tetracycline regulated system, as evidenced by Balklava et al. (Balklava Z. et al. Analysis of tissue transglutaminase function in the migration of Swiss 3T3 fibroblasts: the active-state conformation of the enzyme does not affect cell motility but is important for its secretion. J Biol Chem. 2002 May 10;277(19):16567-75. doi: 10.1074/jbc.M109836200. Epub 2002 Feb 26. PMID: 11867617.). This references teaches a specific fibroblast cell line that has been genetically engineered.
Amount of Experimentation Required. Given the unpredictability of the art, the poorly
developed state of the art with regard to editing various different lines of fibroblasts, and the variability in viability of the genetically modified fibroblasts, the skilled artisan would have to conduct undue, and unpredictable experimentation to practice the claimed invention using the composition comprising the genetically modified fibroblasts. Further, due to the lack of specific guidance in the specification for modifying fibroblasts other than dermal fibroblasts, it would require undue experimentation to practice the breadth of the instant methods as claimed.
Conclusion
Claims 1 and 4 are allowed.
Claims 5 – 11, and 13 – 23 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VYOMA SHUBHAM TIWARI whose telephone number is (571)272-2954. The examiner can normally be reached M-F 8:30 - 5:30 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights