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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-8, and 21-22), and the species election of HIF1AN in the reply filed on 06/25/2025 is acknowledged.
Claims 11,14,17,20, and 24-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/25/2025.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) was filed before the mailing date of the non-final first action on the merits. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 1. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cai et al (Journal of Biological Chemistry, 2018).
Regarding claim 1-2,4-5,and 7, Cai et al teach the use of CRISPR/Cas systems to knockout the HIF1AN gene (referred to as fih ) in zebrafish, which encodes the Factor Inhibiting Hypoxia-inducible factor 1-alpha (FIH-1), a negative regulator of the Hypoxia-Inducible Factor (HIF). (See abstract). Cai et al teach the use of CRISPR/Cas strategy to generate two zebrafish fih mutants, one with an 11-nt deletion in exon 1 of fih and the other mutant having a 14-nt deletion in exon 1 of fih. (See supplementary Fig.S5). Cai et al demonstrate that the expression level of FIH-1 in the second mutant is decreased by more than 70% than in the wild-type.(See supplementary Fig.S5 D). Cai et al further demonstrate that deleting fih in zebrafish increases the expression of the hypoxia-inducible factor (HIFα), wherein the expression level of HIFα in the knockout is higher than the expression level of HIFα in the wild-type. (See supplementary Fig.S6). Cai et al state that “ Using CRISPR/Cas9 to obtain fih-null zebrafish mutants, we noted that the fih deletion makes zebrafish more tolerant of hypoxic conditions than their WT siblings”, demonstrating that FIH-1 is critical for adaptation to acute hypoxia. (See abstract).
Regarding claim 3, It should be noted that Cai et al’s technique employing CRISP/Cas involves the generation of two zebrafish mutants, with the deletion is targeting exon 1 of the fih gene. This differs from instant application, which targets exon 1 of FIH in human genome of mesenchymal cell. ( See experimental example 1 of instant specification). Cai et al disclose an alignment of FIH-1 amino acid sequences between the human and zebrafish. (See supplementary Fig.1). It is noted that the zebrafish fih gene encodes for a 344-amino acid protein that is 79.89% identical to the human HIF1AN/FIH gene. It is clearly obvious that the genetic makeup of the fih gene differs between the two species. Therefore, the design and execution of CRISP-Cas9 for zebrafish would differ from that for humans due to differences in the genome sequences. However, since the strategy of Cai et al involves using CRISPR-Cas9 to mediate nucleotide deletions in exon1 of fih gene in zebrafish, which resulted in more than 70% decrease in FIH-1 expression in the second mutant relative to the wild-type, the engineered gene is presumed to also be lacking one or more of the recited sequences in instant claim. Absent evidence to the contrary and the claim is considered anticipated.
Regarding claim 8, Cai et al also demonstrate that the fih deletion up-regulated several hypoxia-inducible genes in fih null zebrafish exposed to hypoxia including VEGF. (See Figs. 7 and S9). Cai et al do not specifically test for the expression of IL-8 upon fih knockdown; however, the outcome is presumed to be inherent in the teachings of Cai et al since the claimed manipulated cell is anticipated by Cai et al.
Claim Rejections - 35 USC § 103
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1-8, and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al (Journal of Biological Chemistry, 2018), in view of Lee et al ( International Journal of Stem Cells, 2019).
The teachings of Cai et al are set forth above. Cai et al anticipate claims 1-8.
Regarding claim 21-22, Following the discussion of claim 1 above. Cai et al disclose the generation of two mutant zebrafish containing engineered cells, wherein the engineered cells comprising an indel in exon 1 of HIF1AN/FIH, resulting in the knock out HIF1AN in the engineered cells (referred to as fih in Cai et al). Cai et al do not disclose the knockout of HIF1AN in mesenchymal stem cells.
However, Lee et al teach that HIF1, which is negatively regulated by FIH-1, is required to maintain the pluripotency and survival of mesenchymal stem cells (MSCs) by mediating adaptation to hypoxic conditions. Lee et al also disclose that overexpressing the alpha subunit of HIF 1 (HIF 1α) has the potential to improve the therapeutic efficacy of stem cell transplants, as evidenced by recent prior arts. ( See abstract and conclusions).
Furthermore, LV et al demonstrate that HIF1α improves viability and suppresses apoptosis of bone marrow-derived mesenchymal stem cells (MSCs). Specifically, LV et al show that MSCs cultured under hypoxia in vitro exhibit higher HIF1α expression and superior growth and survival status. (See Fig.1). LV et al further demonstrate that HIF1α overexpression in MSCs under normoxia pro-moted viability and inhibited apoptosis, while knocking down HIF1α in MSCs cultured under hypoxia suppressed viability and ele-vated apoptosis. ( See Figs.2-3). According to LV et al, “HIF1α may improve viability and suppress apoptosis of MSCs, implying protective effect on MSC survival under hypoxia, and potentially facilitating the application of MSCs in cell therapy.” ( See abstract).
Taken together, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to combine the teachings of Cai et al, Lee et al, and LV, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Because Cai et al demonstrate how to utilize CRISPR/Cas systems to knock out the HIF1AN gene (referred to as fih ) in zebrafish to promote tolerance to hypoxia. Cai et al’s findings clearly demonstrate that HIF1AN gene is critical for cells adaptability to hypoxia conditions. Lee et al teach that HIF1-mediated adaptation to hypoxia is required to maintain the pluripotency and survival of mesenchymal stem cells (MSCs) under hypoxic conditions. LV et al demonstrate that HIF1α overexpression in MSCs improves survival during hypoxia. Hence, an ordinary skill in the art would be motivated to adapt the CRISPR/Cas system disclosed in Cai et al to knock out the HIF1AN in mesenchymal stem cells in order to increase the level of HIF1α.There is a reasonable expectation of success because increasing the level of HIF1α promotes viability and suppresses apoptosis in MSCs.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-8, and 21-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, and 13,16-19, and 22-24, of copending Application No. 17/792771.
Although the claims at issue are not identical, they are not patentably distinct from each other because copending claims are directed to the use of manipulated cells for treating Alzheimer’s disease, wherein the manipulated cells comprising an engineered gene having an
indel in an HIF1AN gene, the indel is located in exon 1 of the HIF1AN gene. The copending claims further teach that the manipulated cells also exhibit a lower expression of FIH-1 and higher expression level of HIFα than in the WT cells.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638