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 .
Applicant’s election without traverse of Group I in the reply filed on 10/06/2025 is re-acknowledged.
Claims 5-7 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected groups/inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/06/2025.
Claims 1-11 are pending.
Claims 8-11 are new.
Claims 1-4 and 8-11 are under examination on the merits.
Priority
Applicant’s claim of priority to REPUBLIC OF KOREA Application no. 10-2021-0177439, filed 12/13/2021 is acknowledged. Applicant cannot rely upon the certified copy of the foreign priority application to overcome any prior art rejection because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Maintained-Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Withdrawn Objections/Rejections
The objections to claims 1 and 3 are withdrawn as addressed by the corrective claim amendments dated 03/10/2026.
Claim Objections
Claim 4 is objected to because of the following informalities: “…mineralization in in the osteoblast…” should read “…mineralization in the osteoblast …”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 U.S.C. 112(a)
New-New Matter
Claims 1-4 and 8-11 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The examiner is unable to find support for the added limitations in claims 1-4 and 8-11 i.e., “contacting osteoblast progenitor cells or mesenchymal stem cells with a composition comprising a PADI2” as a means for preventing or alleviating senescence. Applicant states that support for the amendment can be found throughout the application. However, the specification never mentions contacting cells with a composition comprising a PADI2. The originally filed claims do not appear to provide support for a method for preventing or alleviating senescence comprising contacting in vitro cells with a composition comprising a PADI2 (noting that the original claim with the closest recitation, still not deemed to support the instantly amended claim scope, is non-elected claim 7). Applicant is required to cancel the new matter in response to this office action.
Should applicant disagree with the examiner’s factual determination above, applicant should provide evidence that either or both of the provisional applications provide support for the invention now claimed in the manner required by 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. This could be accomplished, for example, by pointing to the specific page and line numbers within the specification, which disclose each limitation of the claimed invention.
Maintained-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 1-4 remain rejected and claims 8-11 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
MPEP 2164.01(a) states that in order to determine compliance with the enablement requirement, the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is “reasonable” or is “undue.”
These factors include but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims
Claims 1-3 and 8-10 are broadly directed to a method for preventing or alleviating osteoblast senescence. Claims 4 and 11 are broadly directed to a method for improving differentiation of osteoblasts. The only active step of claims 1-4 and 8-11 is to contact osteoblast progenitor or mesenchymal stem cells with a composition comprising a PADI2 in an implied amount effective bring about either a decreased expression of CCL2, CCL5, and CCL7 or to increase alkaline phosphatase activity and mineralization in osteoblasts (see exemplary claims 1 and 4, respectively). This encompasses a broad range of potential ‘effective amounts’ and compositions comprising PADI2.
The nature of the invention
Claims 1-3 and 8-10 are broadly directed to a method for preventing or alleviating osteoblast senescence. Claims 4 and 11 are broadly directed to a method for improving differentiation of osteoblasts. The claims are directed to biological subject matter which is understood to be complex and often unpredictable.
The state of the prior art
The state of the prior art supports that cellular senescence (osteoblastic or otherwise) is complex and that the scientific understanding of the underlying processes is an area of continuing research to develop our imperfect understanding of said process (see for example, section 3 at pages 4-5 of Zhang et al (Clin. Transl. Med. 2025;15:e70417. wileyonlinelibrary.com/journal/ctm2)). Zhang et al further teach that the scientific community is currently proposing strategies to prevent or treat aging (understood to include senescence of osteoblasts in light of the section heading of section 5) and, while discussing known proposed means, PADI2 is not mentioned (see for example, section 5 at page 22 and pages 22-27). The prior art does not appear to teach contacting cells with a composition comprising a PADI2 protein for preventing of alleviating senescence in vitro.
The level of one of ordinary skill
As the claims are directed to prevention or treatment of senescence or differentiation of osteoblasts, the artisan is presumed to be highly skilled, tending to have an advanced degree (such as a Ph.D. or an M.D.).
The level of predictability in the art
The art teaches that research has determined that a correlation between a biomarker and a disease state does not mean that the biomarker is a drug target. For example, Kempf et al (2006, Cir. Res. 98:351-350) show a correlation between elevated GDF-15 levels and adverse cardiovascular events. Such may suggest that treatment with anti-GDF-15 would be beneficial to patients. However, it was discovered that GDF-15 expression was elevated in response to the cardiovascular event as a way for the body to attempt to protect its tissues from ischemia/reperfusion injury. Accordingly, administration of an anti-GDF-15 agent would have been harmful to patients. Therefore, discovery of a correlation alone is not enabling for a method of treatment. Additionally, markers can be elevated as a result of the disease, or as part of a body’s response to a disease, and cannot be presumed to be causative or contributory to the disease without significant further research. For example, with respect to G-protein coupled receptor perturbations in the disease hypertension, "it has been difficult to determine whether they are the cause or consequence of the disease" (Feldman, 2002, Molecular Pharmacology. 61(4): 707-709). With respect to temporal lobe epilepsy, Janigro (2008, Epilepsy Currents 8(1): 23-24) teaches that "[a]s with many pathological findings in neurodegenerative diseases, it is difficult to determine if the changes are a cause or consequence of epileptic seizures" (p. 23).
Additionally, Chen et al (BioRiv preprint posted February 6, 2022, ORCID: https://orcid.org/0000-0002-9534-6199; doi: https://doi.org/10.1101/2022.01.30.478394) teach that simple elevation of protein/gene expression level in a disease state does not mean the gene/protein is causal for the disease nor targeting it would be effective for therapeutic efficacy. The increase in expression might only suggest it is correlated with disease progression. Differentiating “causality” from “correlation” is a crucial step in identifying a promising disease target (see for example, the first paragraph of the Introduction at page 3). Furthermore, Bryant et al (THE LANCET, Infectious Diseases Vol 4 February 2004, https://doi.org/10.1016/S1473-3099(04)00930-2) teach that knowledge that a gene is expressed under a particular condition is not an answer in itself but only the first step in understanding. For example, whether expression of a gene is vital for host defense or involved in tissue injury requires further investigation. In addition, expression of a gene does not always translate into production of a protein. Although gene expression reveals nothing directly about translational and post-translational events, protein activation status alterations can and do frequently alter the expression of downstream target genes (see for example, column 2 of page 110).
Furthermore, the state of the art supports that cell differentiation is complex and that influencing said process is a highly skilled and unpredictable endeavor subject to a multiplicity of factors (see for example, Sanchez-Alvarado et al (Cell 157, March 27, 2014, Elsevier Inc; see for example, the abstract) and Menezes et al (Nat Commun 16, 5000 (2025), https://doi.org/10.1038/s41467-025-60348-6; see for example, the abstract). Zhu et al (Cell Discov 10, 71 (2024). https://doi.org/10.1038/s41421-024-00689-6) discuss the state of the art regarding cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis discussing various known and implicated genes and proteins. PADI2 is not mentioned as being understood as of 2024 as being involved in alkaline phosphatase activity or mineralization in the process of osteoblast progenitor/mesenchymal stem cell differentiation to osteoblasts.
(F) The amount of direction provided by the inventor
Applicant does not disclose a single composition comprising a PADI2 (which is a protein product as presently drafted in the claims). Applicant further fails to disclose any instance of contacting cells with a composition comprising a PADI2 protein. Applicant instead discloses data supporting a correlation between decreased PADI2 and increase cell senescence (primarily in the form of knockdown and siRNA data). It is noted that Applicant’s own discussion and drawings (see for example, figure 14 at page 15 of the 03/10/2026 drawings) would suggest that PADI2 functions intracellularly, such that contacting a cell with a PADI2 protein would not appear to have the same effect as Applicant has not shown sufficient (or any) uptake of extracellular PADI2 or how PADI2 would function to exert the claimed effects intercellularly. Applicant only provides knock-in/knock-out data which, as the art cited above teach, is not sufficient to establish a causative role between a protein (such that replacement or use of the protein would treat the condition) and a condition/disease state. Applicant has further not supplied an amount sufficient for contacting the cells with to bring about the claimed effects because at no point does Applicant mention contacting cells in vitro with a composition comprising a PADI2 protein/enzyme. Applicant instead relies upon a limited data showing that Application of H2O2 or PADI2 gene knockdown/knockout results in cells with increased senescence/decreased mineralization and differentiation. This does not support or reasonably suggest that application of a composition comprising the PADI2 protein would effect osteoblast progenitor/mesenchymal stem cell differentiation by effecting an increase in alkaline phosphatase and mineralization and/or a decrease in CCL2, CCL5, and/or CCL7.
The existence of working examples
There are no working example provided in the instant disclosure because a PADI2 protein is never used, disclosed, or contacted with cells.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
The case is directed to biological subject matter, which is by nature complex. There are no working example provided and the state of the art fails to step in to provide enablement where the instant disclosure is lacking. The artisan would be forced into burdensome experimentation so as to effectively invent what applicant only suggests may be possible.
Thus, in light of the contradictory findings in the prior art, discovery of a correlation alone is not enabling for a method of prevention/alleviation of senescence or for improving osteoblast differentiation. Data supporting that a knockout/knockdown promotes senescence is not sufficient to support that contacting cells with the protein product of the gene would function to prevent or alleviate senescence, as measured by increasing alkaline phosphate activity and/or mineralization and/or decreasing expression and secretion of one or more of CCL2, CCL5, and CCL7, as claimed.
Maintained-35 U.S.C. 112(b)
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.
Claims 1-4 remain rejected and claims 8-11 are newly 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 1 is indefinite because when the claim recites contacting cells with a composition comprising PADI2, there is an implied amount/concentration of PADI2 to be contacted which would be sufficient to exert/bring about the recited effects of inhibiting secretion of one or more of CCL2, CCL5, and CCL7. This amount/concentration is never specified. Applicant provides no examples of contacting a composition comprising a PADI2 (a protein product) to cells by which said amount/concentration may be further described or disclosed. The artisan is left to devise their own compositions and means for determining potentially conflicting amounts which may arguable be encompassed by the claim as drafted. Therefore, the metes and bounds of the claim are indefinite.
Claims 2-3 and 8-10 incorporate through dependency and fail to remedy the above noted ambiguities of independent claim 1.
Claim 3 is further indefinite because the term “decreased” in claim 3 is a relative term which renders the claim indefinite. The term “decreased” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what measurement and what degree of change would be encompassed. It is further unclear what the decrease is from.
Claim 4 is indefinite because when the claim recites contacting cells with a composition comprising PADI2, there is an implied amount/concentration of PADI2 to be contacted which would be sufficient to exert/bring about the recited effects of increasing alkaline phosphatase activity and mineralization. This amount/concentration is never specified. Applicant provides no examples of contacting a composition comprising a PADI2 (a protein product) to cells by which said amount/concentration may be further described or disclosed. The artisan is left to devise their own compositions and means for determining potentially conflicting amounts which may arguable be encompassed by the claim as drafted. Therefore, the metes and bounds of the claim are indefinite.
Claim 11 incorporates through dependency and fails to remedy the above noted ambiguities of independent claim 4.
Claim 4 is further indefinite because the term “increase” in claim 4 is a relative term which renders the claim indefinite. The term “increase” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what measurement and what degree of change would be encompassed. It is further unclear what the decrease is from.
Claim 11 incorporates through dependency and fails to remedy the above noted ambiguities of independent claim 4.
Applicant’s Arguments and Responses:
A. Applicant requests withdrawal of the objection to the drawings containing color because a petition for color drawings was filed on 03/10/2026 at page 8 of the03/10/2026 remarks.
Response: The Examiner thanks Applicant for filing said petition, but is unable to withdraw the objection to the drawings because the Petition for Color Drawings has not yet been accepted.
B. Applicant argues for withdrawal of the rejections under 35 USC §112(a) for lack of enablement citing to knockout and knockdown data.
Response: Applicant argues their knockout and knockdown data amount to more than a mere correlation. This may be true if the claims pertained to a knockdown/knockout of the PADI2 gene. However, what is claimed is a method for preventing or alleviating osteoblast senescence in vitro, comprising contacting osteoblast progenitor cells or mesenchymal stem cells with a composition comprising a PADI2. As Bryant et al points out, expression of a gene does not always correlate with production of a protein product. Furthermore, by a reading of Applicant’s own disclosure, it would appear that PADI2 is acting intracellularly, such that it is unclear if contacting cells with extracellular PADI2 would have the claimed effect. Applicant has potentially discovered link between the gene encoding PADI2 and senescence, but claims a method of preventing or treating senescence by contacting cells with a composition comprising a PADI2. Applicant asserts that Zhang et al’s failure to mention PADI2 is not a teaching that PADI2 could not function as claimed. The Examiner does not dispute this. Zhang et al was not cited to show that Applicant’s method does not work. Zhang et al was cited (similarly to the newly cited Zhu et al reference) to show that the state of the art cannot step in to provide enablement where Applicant’s disclosure fails to do so. While Applicant argues that the degree of experimentation required by the artisan is not undue, Applicant supplies no evidence and/or rationale to support this conclusion. The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP 2145 (I). Therefore, the rejections of record as presented in this Office Action are maintained at this time.
C. Applicant argues their amendments overcome the rejections under 35 USC §112(b) and request withdrawal of said rejections.
Response: The rejections have been adjusted to account for Applicant’s amendments which do not sufficiently clarify the claim scope for reasons iterated in the rejections under 35 USC §112(b) above. The rejections are therefore maintained at this time.
Conclusion
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 ASHLEY GAO whose telephone number is (571) 272-5695. The examiner can normally be reached on Monday- Friday 8-5pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s
supervisor, Gregory Emch can be reached on (571) 272-8149. The fax phone number for the
organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent
Application Information Retrieval (PAIR) system. Status information for published applications
may be obtained from either Private PAIR or Public PAIR. Status information for unpublished
applications is available through Private PAIR only. For more information about the PAIR
system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR
system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would
like assistance from a USPTO Customer Service Representative or access to the automated
information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights