DETAILED ACTION
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/8/2026 has been entered.
Claim Status
As of the Final Office Action mailed 1/14/2026, claims 10-12 and 14 were pending.
In Applicant's Response filed on 4/8/2026, claim 12 was amended and claims 10-11 and 14 were canceled.
As such, claim 12 is pending and has been examined herein.
Withdrawn Objections/Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections or rejections not specifically reiterated are hereby withdrawn.
New Grounds of Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 12 is rejected 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.
Claim 12 recites, inter alia, “referred to as Phy-RIND-EDSBs and . . . referred as Youth-DNA-GAPs”. It is unclear if these are claim embodiments or examples. It is unclear whether the limitations following the phrase are part of the claimed invention. Thus, the claim is indefinite.
Claim Interpretation
Claim 12 recites “overexpressing the encoded peptide”. The examiner is interpreting that the overexpression is a result of the transfection step absent evidence to the contrary.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fumero et al (US20110052493 A1, 11/09/2009; published 3/3/2011) as evidenced by Mutirangura (IntechOpen, 31 Dec 2018; p. 1-16; of record) and in view of He et al (CN101691580A, 28 Sept 2008; published 15 Feb 2012; of record).
Fumero teaches a method of producing a polypeptide variant of HMGB1 Box-A or a biologically active fragment thereof comprising introducing a nucleic acid molecule into a host and culturing the cell under conditions in which the encoded polypeptide variant is expressed (see claim 20 of Fumero). The reference also teaches that the nucleic acid is in a vector (see claim 19 of Fumero and para 119) (“” as in instant claim 12).
The difference between Fumero and the instant invention is that it does not explicitly disclose SEQ ID NO. 1 as instantly claimed nor that the peptide produces Phy-RIND-EDBS and Youth-DNA-GAPs.
Mutirangura teaches that global hypomethylation causes a reduction in Phy-RIND-EDSBs and that the reduction in Phy-RIND-EDSBs causes DNA damage (Introduction para 1). Endogenous DNA double-strand break (EDSB) are found in all cells, including nondividing cells (replication-independent EDSBs; RIND-EDSBs). The reference teaches majority of RIND-EDSBs possess physiological functions, namely, physiologic RIND-EDSBs (Phy-RIND-EDSBs), as epigenetic marks in maintaining genomic stability. Interestingly, Phy-RIND-EDSBs in yeast decrease when yeast cells age resulting in renaming Phy-RIND-EDSBs in accordance with their role as youth-associated genomic-stabilizing DNA gaps (Youth-DNA-GAPs) (i.e., Phy-RIND-EDSB is the same as Youth-DNA-GAPs) (Introduction para 3). Hypomethylated genome of the elderly reduces Phy-RIND-EDSBs and this reduction causes DNA damage (same para). The accumulation of DNA damage initiates DDR and consequently drives the cellular aging process (Figure 1; same para). The reference teaches that there is low levels of RIND-EDSBs in cells lacking high-mobility group box (HMGB) proteins (i.e., cells lacking at least HMGB1 Box A) and Sir2 (Section 3.2, para 1). Thus, HMGB proteins and Sir2 play roles in producing and maintaining Phy-RIND-EDSBs (same para). Phy-RIND-EDSB levels in the elderly should be low. We found low levels of RIND-EDSBs in chronologically aging yeast and in the human cancer cells, HeLa and SW480, which are cervical cancer and colon cancer cell lines, respectively (Section 3.5, para 3). The reduction in the Phy-RIND-EDSB complex will increase the production of DNA damage (section 3.7, para 1). Therefore, aging cells have to repair DNA damage more often than younger cells (same para). As a result, more DNA repair machinery is required for older cells. Consequently, DNA repair substrates are consumed more quickly than they are produced, resulting in DNA repair defects in the elderly (same para).
He teaches a novel fusion protein for human HMGB1 A box (abstract). The reference teaches a recombinant plasmid comprising HMGB1 A box and an acidic tail, wherein the HMGB1 A box is SEQ ID NO: 1 (see claims 1 and 3 of He). HMGB1 can exist in multiple parts such as the nucleus, cytoplasm and extracellular of eukaryotes (Background para 1). It was originally recognized as a nuclear protein, which can non-specifically bind to the minor groove of DNA molecules and stabilize nucleosomes. It also participates in life activities such as cell differentiation, DNA replication, transcription, recombination and repair (same para). SEQ ID NO: 1 of He and instant SEQ ID NO: 1 are 99.6% similar.
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Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to introduce a vector containing HMGB1 A box into cells as taught by Fumero, where RIND-EDSBs and Youth-DNA-Gaps are produced as evidenced by Mutirangura, to arrive at the instantly claimed invention. Mutirangura shows that HMGB1 proteins produce and maintain RIND-EDBS and Youth-DNA-Gaps. One of ordinary skill would have been motivated to perform the method of Fumero with a reasonable expectation of improving DNA repair defects and decreasing production of DNA damage as taught by the prior art. One of ordinary skill in the art would have understood the claimed HMGB1 Box A exhibits same/similar characteristics as disclosed by Mutirangura (e.g., in producing and maintaining Phy-RIND-EDSBs, etc.) and is capable of similar biological effects.
Response to Arguments
Applicant's arguments regarding the He and Mutirangura reference have been fully considered but they are not persuasive.
On p. 11-12 of Remarks, Applicant argues, in sum, that the He reference does not disclose induction or production of Phy-RIND-EDSBs and Youth-DNA-Gaps utilizing HMGB1 box A expression. Applicant also argues that the Mutirangura reference provides scientific discussion of biological significance of Youth-DNA-Gaps but does not disclose a method of producing them through expression of a peptide encoded by a vector nor does it teach or suggest the use of Box A domain to induce their expression. Applicant further argues that even if, arguendo, one of ordinary skill would combine He and Mutirangura, the combination would still fail to disclose the instant invention of claim 12. Applicant argues that there is no teaching, suggestion, or motivation to select Box A of HMGB1, express it in cells using a vector, and induce production of Phy-RIND-EDSBs and Youth-DNA-GAPs and that the examiner utilized impermissible hindsight reconstruction. On p. 12-13 of Remarks Applicant further argues that the present invention as claimed in the amended claim 12 is based on the discovery of a previously unrecognized genomic phenomenon involving the production of Phy-RIND-EDSBs and Youth-DNA-GAPs, and that the expression of the HMGB 1 Box A domain peptide can induce the production of the aforementioned specific endogenous genomic structures, Phy-RIND-EDSBs and Youth- DNA-GAPs, associated with genomic stability in youthful cells. In fact, historically, DNA double-strand breaks have largely been viewed in the art as harmful lesions associated with DNA damage and genomic instability. The instant Application instead demonstrates that certain physiologic replication-independent endogenous DNA double-strand breaks function as part of a genomic stabilization mechanism associated with youthful cellular states. Thus, the discovery that expression of the HMGB1 Box A domain peptide increases the production of these genomic structures in the present invention of the instant Application represents a novel biological insight, which is not disclosed, taught, or suggested by the cited prior art. Applicant argues that even assuming, arguendo, that the prior art disclosed expression of HMGB 1-related peptides in certain contexts, there is no teaching or suggestion in the art that would motivate a person of ordinary skill to use the Box A domain of HMGB 1 for the purpose of inducing production of the genomic structures recited in the amended claim 12. Applicant argues that even where a molecule itself may be known in the art, it is well established that a newly discovered and non-obvious biological property or function of that molecule may support patentability when the prior art neither recognized nor suggested that function. As discussed above, in the instant case, the prior art does not disclose, teach, or suggest that expression of the HMGB1 Box A domain peptide results in the production of physiologic replication-independent endogenous DNA double- strand breaks (Phy-RIND-EDSBs) and youth-associated genomic-stabilizing DNA gaps (Youth-DNA-GAPs) in the nucleus of cells.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). The examiner also notes that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977) (MPEP 2112(I)).
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, newly cited Fumero teaches the introduction of HMGB1 Box A containing vector into cells to induce expression of the peptide and the teachings of Mutirangura provide one of ordinary skill teaching, suggestions, and motivations that the use of HMGB1 proteins (which would include Box A) would produce and maintain Phy-RIND-EDSBs (and subsequently Youth-DNA-Gaps) in cells in which it is expressed.
Applicant argues that the present invention reveals a beneficial biological role for specific endogenous double-strand breaks that represents a counterintuitive and previously unrecognized mechanism, however, previously cited Mutirangura states “[i]independent of DNA replication, the eukaryotic genome retains a certain amount of endogenous DNA double-strand breaks(EDSBs), called physiologic replication-independent EDSBs (Phy-RIND-EDSBs), that possess a physiological function . . . and low levels of Phy-RIND-EDSBs decrease cell viability and increase DNA damage. Thus, Phy-RIND-EDSBs have a biological role as youth-associated genomic-stabilizing DNA gaps,” “DNA methylation stabilizes the genome by homing Youth-DNA-GAPs, Phy-RIND-EDSBs, and that the gaps extended the stabilizing effect to the entire genome,” and “Phy-RIND-EDSBs are Youth-DNA-GAPs epigenetic marks that prevent genomic instability in eukaryotic genomes.” (see Mutirangura disclosure throughout). The mechanisms/beneficial role of endogenous DSBs that Applicant argues was known in the prior art given the disclosure of Mutirangura. Thus, Applicant’s arguments are not persuasive.
Conclusion
No claim is allowed.
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/G.R./Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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