NEW SPLICE VARIANT ISOFORM OF VEGF

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 . Status of the Application 1. Claims 1-19 are pending and subject to examination on the merits. Claims 5-19 are withdrawn from consideration as being drawn to non-elected subject matter. Claims 1-4 are subject to examination on the merits. Examiner/Locale 2. The location and examiner assigned to the instant Application at the USPTO has changed. Please direct all further correspondence to Art Unit 1656 and to the Examiner signed below Election/Restrictions 3. Claims 5-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected groups II-IX, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 19 January 2026. The applicant argues that the amendment to claim 1 negates the previous art teaching the shared technical feature breaking the unity of inventions. Specifically, the applicant amended claim 1 to recite an isolated splice variant isoform of VEGF with at least 83% (previously 80%) identity to the amino acid sequence of SEQ ID NO: 1. The previously cited art, Uniprot UP10000E0A1F9 disclosed a polypeptide with 81% sequence identity to SEQ ID NO: 1. Although, this amendment does negate the cited art, unity is still broken due to the shared technical feature being taught. Specifically, the recitation of an isolated RNA transcript with at least 80% identity to SEQ ID NO: 4, resulting from the transcription of the cDNA with at least 80% sequence identity to SEQ ID NO: 3, which encodes the splice variant of claim 1, is known in the art. Specifically, Bancel et al (Bancel et al., 2015, US8999380—cited herein) teaches a sequence with 92.5% sequence identity to SEQ ID NO: 4 (See Supplemental file: 20260924_094456_us-18-250-569a-4.rni). The requirement is deemed proper and therefore made Final. Priority 4. Acknowledgment is made for the Applicant’s claim for domestic priority based on the US provisional application PRO 62/849,794 filed 17 May 2019. Information Disclosure Statement 5. The information disclosure statements (IDS) submitted on 07 September 2021 and 12 July 2022 have been considered by the examiner. See initialed and signed PTO/SB/08’s. Drawings 6. The drawings are objected to because Fig. 3A recites “pyrimidin,” which should be amended to “pyrimidine.” Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Nucleotide and/or Amino Acid Sequence Disclosures Compliance with Sequence Rules 7. The sequence listing, filed in computer readable form (CRF) and paper copy on , has been received and entered. This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). However, this application fails to fully comply with the requirements of 37 C.F.R. § 1.821 through 1.825; Applicants’ attention is directed to the final rulemaking notice published at 55 FR 18230 (May 1, 1990), and 1114 OG 29 (May 15, 1990). The following parts of the Drawings contain sequences that contain four or more specifically defined amino acids without any corresponding SEQ ID NO: a) Fig. 3A recites “cdxprr” without a corresponding SEQ ID NO in the Drawings or the Brief Description of the Drawings. b) Fig. 3A’ recites 6 sequences without corresponding SEG ID NOs in the Drawings or the Brief Description of the Drawings. c) Fig. 3B recites 8 sequences in an alignment without corresponding SEQ ID NOs in the Drawings or the Brief Description of the Drawings. d) Fig. 15 recites 44 sequences without corresponding SEQ ID NOs in the Drawings or the Brief Description of the Drawings. Applicants must amend the specification to identify the sequences appropriately by SEQ ID NO:. — See also MPEP 2422. Specification 8. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (p. 31, line 38). 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 Objections 9. Claims 1-4 are objected to because of the following informalities: the recitation of “VEGF” without first defining the abbreviation. Appropriate correction is required. Claim Rejections - 35 USC § 101 10. 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. 11. Claims 1-3 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a natural phenomenon) without additional elements that integrate the judicial exception into a practical application. An analysis with respect to the claims as a whole reveals that they do not include additional elements that integrate the judicial exception into a practical application. See MPEP 2106. Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of the following steps: Step (1) whether the claim is directed to one of the four categories recited in §101 (process, machine, manufacture or composition of matter); Step (Revised 2A - Prong 1) do the claims recite an abstract idea (mathematical concepts, mental processes or method of organizing human activity), law of nature or natural phenomenon; Step (Revised 2A - Prong 2) do the claims recite additional elements that integrate the judicial exception into a practical application; and Step (2B) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. (See 2019 Revised Patent Subject Matter Eligibility Guidance (2019 PEG)). Step 1: Yes; the claims are directed to a composition of matter. Step 2A – Prong 1: Yes, the claims recite a natural phenomenon, namely, a naturally occurring splice variant isoform of VEGF. Step 2A – Prong 2: No, the claims do not recite any additional elements that integrate the judicial exception into a practical application because the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed with the naturally occurring isolated splice variant isoform of VEGF. For example, the instant specification states: “The present invention is based on the discovery by the inventors of the existence of a new alternative splice acceptor site in the seventh intron (p. 4, lines 38-39).” “The present inventors have identified a new alternative splice acceptor site, notably present in the last intron of the VEGF pre-mRNA resulted in the insertion of 23 bases that shifted the open reading frame giving rise to a human VEGF isoform minus the signal peptide, of 222 amino acids. This novel isoform has been designated VEGF222/NF. VEGF222/NF stimulates endothelial cell proliferation and vascular permeability through VEGFR2 activation (p. 10, lines 19-24).” “The resulting new alternative splicing leads to the production of the VEGF222/NF. VEGF222/NF displayed physiological pro-angiogenic, pro-permeability and pro-migratory properties. Its expression was evidenced in several cancer cell lines including ccRCC (p. 21, lines 30-32).” Thus, claims 1-3 read on the naturally occurring product, VEGF222/NF, since claims 1-3 are drawn to a sequence with at least 83% identity to SEQ ID NO: 1 (claim 1), an isoform comprising SEQ ID NO: 1 (claim 2), and VEGF222/NF consists of SEQ ID NO: 1 (claim 3). This sequence was not produced by the applicant. The sequence is resultant from a naturally occurring alternative splice site described by the applicant. The RNA sequence was not altered in any way, and no other additional items were introduced to create this splice variant. Step 2B: As noted in answering that of 2A – This judicial exception is not integrated into a practical application because the VEGF splice variant is detectable in human tumors and the resulting amino acid sequence/polypeptide is resultant from the utilization of a natural splice site, of which the applicant discovered, i.e. did not manufacture. Allowable Subject Matter 12. Claim 4 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Conclusion 12. Claims 1-3 are rejection. Claim 4 is objected. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm. 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, Manjunath Rao can be reached on (571) 272-0939. 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. /CIARA A MCKNIGHT/Examiner, Art Unit 1656 /SUZANNE M NOAKES/Primary Examiner, Art Unit 1656