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 .
Information Disclosure Statement
The information disclosure statements (IDS) comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered as to the merits.
Status of the application
Receipt of applicant’s remarks filed on 11/03/2025 are acknowledged.
However, applicants’ arguments for the previous 103 rejections are found not persuasive. Accordingly, the previous rejections are maintained. Please see the examiners response to applicants arguments below.
Response to Arguments
Applicants’ argue that Ma-Lauer does not teach or suggest administration of p53, under any form or by any route, to virally infected cells. Its experiments are entirely in vitro and concern endogenous p53 levels in cells that naturally express or lack the p53 gene (p53+/+ vs. p53-/-). The reference compares intracellular outcomes following infection but never delivers exogenous p53 protein or nucleic acid to those cells. The only instance of exogenous p53 in Ma-Lauer is an overexpression of p53-GFP, which was performed in non-infected cells to visualize p53 localization and confirm proteasomal degradation. This assay was a mechanistic control, not an antiviral or therapeutic test, and it provides no basis for inferring that delivery of p53 to infected cells would have therapeutic benefit.
Ma-Lauer showed the evidence that p53 inhibits replication of SARS-CoV in human HCT116 cells, wherein HCT116 cells were infected with SARS-CoV, as explained in the rejection. In other words, p53 is shown to inhibit replication of SARS-CoV, and so a skilled person in the art would be motivated to extrapolate administration of p53 to treat viral infection in animals. Applicants fail to show or explain, why the shown data of Ma-Lauer cannot extrapolated or develop a method to treat viral infection in a subject in need there of?
Applicants further argue that Tendler likewise does not provide the missing teaching. Tendler describes cell-derived vesicles containing wild-type p53 for oncology applications, specifically restoration of tumor-suppressor function in cancer cells. It contains no disclosure of viral infection, antiviral mechanisms, or any rationale that vesicle-delivered p53 could overcome virus-induced p53 degradation. Substituting Tendler's cancer-therapy vesicles into Ma-Lauer's infection model is therefore scientifically unfounded and lacks any rational motivation or reasonable expectation of success.
The purpose of Tender is to show the advantages of cell-derived vesicles in drug delivery. Further, Tender exemplifies cell derived vesicles comprising an active wild-type p53, wherein microvesicles serve as signaling payloads containing cell-specific collections of proteins, lipids and genetic material that are transported to other cells where they can alter cell' s function and physiology. In other words, ‘cell-derived vesicle’ based technology is a tool to deliver drug to the target area, wherein drug can be organic compound or peptide or microRNA etc., and it does not matter whether the disease is cancer or viral infection.
So, the technology shown by Tender can be extrapolated to treat other diseases by administering a drug, wherein the drug is conjugated to cell-derived vesicles, 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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
I. Claims 1, 5-6, 8, 12-13, 16, 20-21, 24-25, 30-31 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Ma-Lauer (PNAS, 2016, Aug 12, E5192-E5201; see applicants filed IDS dated 12/04/2022) in view of Tendler (WO 2018/173059 A1; see applicants filed IDS dated 12/04/2022), Aloni-Grinstein (Cancers, 2018, 10, 178, 1-11; see applicants filed IDS dated 12/04/2022) and Lazo (Rev.Med.Virol., 2011, 21, 285-300).
For claim 1:
Ma-Lauer teaches a method, wherein p53 inhibits replication of SARS-CoV, wherein the method comprises infecting human ACE2-transgenic p53-expressing HCT116 cells (HCT116/ACE2 p53+/+) as well as p53 knockout cells (HCT116/ACE2 p53−/−) with SARS-CoV, and viral replication was monitored by real-time PCR., SARS-CoV grew to an ∼1,000-fold higher titer in p53−/− cells compared with p53+/+ [see abstract, section P53 Inhibits Replication of a SARS-CoV in pages E5196-E5197 and Fig.6].
Above is interpreted as a method of treating viral infection, wherein the subject is cells. Alternatively, p53 is shown to inhibit replication of SARS-CoV, and so a skilled person in the art would be motivated to extrapolate administration of p53 to treat viral infection in animals.
The difference is that Ma-Lauer is silent on ‘cell-derived vesicles comprising wild-type p53’. However, applicants already acknowledges in their specification that drug delivery systems comprising multilamellar lipid vesicles conjugated to p53, and the use of same for therapy and their advantages.
In addition, the deficiency can be cured by the following teachings of Tender:
Tender teaches cell derived vesicles comprising an active wild-type p53, wherein microvesicles serve as signaling payloads containing cell-specific collections of proteins, lipids and genetic material that are transported to other cells where they can alter cell' s function and physiology. Exosomes, microvesicles of about 40-200 nm in diameter, have pleiotropic biological functions, including immune response, antigen presentation, intracellular communication, and cell to cell transfer of RNA and proteins. Exosomes are typically formed when cellular compartments known as multivesicular endosomes (MVE) or multivesicular bodies (MVB) bud inward to form small internal vesicles containing proteins, mRNAs and miRNA from the cytoplasm. These internal vesicles are released as exosomes when MVE fuse with the cell membrane or, alternatively fuse with lysosomes. Tender further states that recently, experiments with exosomes as means of chemo- and other therapy delivery vehicles were reported, e.g. as means for delivery of drugs, microRNAs, siRNAs, and antigens to target recipient cells in order to treat tumorigenesis or metastasis [Tickner J.A. et al., Front Oncol. (2014) 4: 127; Kim M.S. et al. Nanomedicine: Nanotechnology, Biology and Medicine. (2016) 12(3): 655- 664; Yim et al, Nature Communications (2016) 7: 12277]. [See page 1 and Summary of Invention].
Therefore, a skilled person in the art would be motivated to replace p53 in the teachings of Ma-Lauer with cell-derived vesicles comprising wild-type p63 from the teachings of Tendler and arrive at applicants claimed invention with a reasonable expectation of success.
For claim 5:
Ma-Lauer teaches SARS-CoV, which is a RNA virus.
For claim 6:
Ma-Lauer silent on viral infection caused by DNA virus. However, the following art teaches nexus between p53 and its antiviral activity on viral infection caused by DNA viruses:
Aloni-Grinstein teaches small DNA viruses, Adenoviruses and SV40, are able to manipulate the host cells by the binding of their viral proteins, E1A and SV40 T-antigen, to the Rb, and this binding releases Rb from E2F, leading to E2F transcriptional activation that mediates S phase entrance. p53 as the “guardian of the genome”, senses this aberrant S phase movement and acts to induce apoptosis, and in another study, eliminating p53 activity, the viral T-antigen or the adenovirus E1B proteins bind p53 and by that inactivate it, allowing the progression into S-phase.
Aloni-Grinstein further teaches that immediately after SV40 infection, activated p53 is noticed only in cells that do not express SV40 viral proteins, suggesting a p53-dependent decision between abortive and productive infection. These p53 host defense mechanisms did not rely on apoptosis, cell cycle arrest, or induction of interferon-stimulated genes, but rather on binding competition between p53 and Sp1, a host protein, which is essential for SV40 assembly. [See abstract, section 2 in pages 2-3 and Table 1].
Further, Lazo teaches that pharmacological rescue of p53 functions might help to control viral infections and teaches effect of p53 on DNA viruses, viz., papoviruses and adenoviruses etc. [see section Interaction of viral proteins with p53 in pages 288-289].
For claim 8:
Ma-Lauer teaches that p53 inhibits replication of SARS-CoV, which is a coronavirus.
For claim 12:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches that the cell derived vesicles comprises exosomes [see page 5, lines 5-6].
For claim 13:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches
that cell derived vesicles are essentially devoid of intact cells [see page 5, lines 13-14].
For claims 16, 20 and 21:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches that wherein the cells are animal tissue, wherein the animal tissue comprises eye tissues, wherein eye tissue comprises corneal epithelium tissue, wherein corneal epithelium tissue comprises corneal epithelial cells [see page 5, lines 15-20].
For claims 24-25:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches that the cells are healthy cells and cells are not genetically non-modified cells [see page 6, lines 1-2].
For claims 28 and 30:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches that cells are treated with DNA damaging agent to activate p53 [see page 5, lines 28-30], and wherein DNA damaging agent phosphorylates p53 [see page 11, lines 18-19 and 30-31].
For claim 31:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches that wherein outer surface of the cell derived vesicles comprises a heterologous moiety for targeted delivery of the cell derived vesicles to a target cell [see page 5, lines 9-10].
For claim 38:
Ma-Lauer silent on human subject. However, Ma-Lauer established a fact that p53 inhibits viral infection in human cell lines. This can be interpreted as ‘subject is human’. Alternatively, based on the findings from Ma-Lauer, a skilled person in the art can extrapolate teachings of Ma-Lauer to human subject in light of well established delivery technologies.
Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e, applicants individual components in the claimed method, were known in the prior art, and one skilled person in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art.
The motivation to combine the art can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and to make the instantly claimed method with a reasonable expectation of success.
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983).
II. Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Ma-Lauer (PNAS, 2016, Aug 12, E5192-E5201; see applicants filed IDS dated 12/04/2022) in view of Tendler (WO 2018/173059 A1; see applicants filed IDS dated 12/04/2022).
Ma-Lauer teaches a method, wherein p53 inhibits replication of SARS-CoV, wherein the method comprises infecting human ACE2-transgenic p53-expressing HCT116 cells (HCT116/ACE2 p53+/+) as well as p53 knockout cells (HCT116/ACE2 p53−/−) with SARS-CoV, and viral replication was monitored by real-time PCR., SARS-CoV grew to an ∼1,000-fold higher titer in p53−/− cells compared with p53+/+ [see abstract, section P53 Inhibits Replication of a SARS-CoV in pages E5196-E5197 and Fig.6].
Above is interpreted as a method of inducing cell cycle arrest and/or apoptosis of a viral infection.
The difference is that Ma-Lauer is silent on ‘cell-derived vesicles comprising wild-type p53’. However, applicants already acknowledges in their specification that drug delivery systems comprising multilamellar lipid vesicles conjugated to p53, and the use of same for therapy and their advantages.
In addition, the deficiency can be cured by the following teachings of Tender:
Tender teaches cell derived vesicles comprising an active wild-type p53, wherein microvesicles serve as signaling payloads containing cell-specific collections of proteins, lipids and genetic material that are transported to other cells where they can alter cell' s function and physiology. Exosomes, microvesicles of about 40-200 nm in diameter, have pleiotropic biological functions, including immune response, antigen presentation, intracellular communication, and cell to cell transfer of RNA and proteins. Exosomes are typically formed when cellular compartments known as multivesicular endosomes (MVE) or multivesicular bodies (MVB) bud inward to form small internal vesicles containing proteins, mRNAs and miRNA from the cytoplasm. These internal vesicles are released as exosomes when MVE fuse with the cell membrane or, alternatively fuse with lysosomes. Tender further states that recently, experiments with exosomes as means of chemo- and other therapy delivery vehicles were reported, e.g. as means for delivery of drugs, microRNAs, siRNAs, and antigens to target recipient cells in order to treat tumorigenesis or metastasis [Tickner J.A. et al., Front Oncol. (2014) 4: 127; Kim M.S. et al. Nanomedicine: Nanotechnology, Biology and Medicine. (2016) 12(3): 655- 664; Yim et al, Nature Communications (2016) 7: 12277]. [See page 1 and Summary of Invention].
Therefore, a skilled person in the art would be motivated to replace p53 in the teachings of Ma-Lauer with cell-derived vesicles comprising wild-type p63 from the teachings of Tendler and arrive at applicants claimed invention with a reasonable expectation of success.
Conclusion
THIS ACTION IS MADE FINAL. 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 SUDHAKAR KATAKAM whose telephone number is (571)272-9929. The examiner can normally be reached 8:30 am to 5 pm.
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658