DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-16 are pending in the instant application.
Information Disclosure Statement
The IDS forms received 7/26/2024 and 11/22/2024 are acknowledged and the references cited therein have been considered.
Claim Objections
Claims 5-13 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only, and cannot depend from any other multiple dependent claim, whether directly or indirectly. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
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 14 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.
Regarding claim 14, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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 and 14-16 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 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.
Applicant has broadly claimed methods of treating or preventing viral infections or complications arising from viral infections by administering plasmacytoid dendritic cells (pDC). The broadest claims simply recite administering pDC, while dependent claims add additional limitations to the cells such as reduced expression of IL-6 (claims 2, 3, and 16) due to a deletion or disruption of toll-like receptor 2 (TLR2). To support such breadth, the specification discloses data from experiments wherein applicant demonstrated that pDC elaborate cytokines in response to coculture with SARS-CoV-2 isolates, with data being presented suggesting that the TLR7 pathway was important for elaboration of highly protective cytokines including IFNalpha while TLR2 was responsible for producing IL-6 based upon studies done with genetic knockouts made using Crisper/Cas9 (example 1). Given that the literature reports that in SARS-CoV-2 patients, high IL-6 titer correlates with worse disease prognosis including development of cytokine storm, applicant hypothesizes that genetically altering pDC to remove IL-6 production via deletion of TLR2 will allow for the delivery of pDC to a patient that can elaborate helpful cytokines including IFNalpha to resolve COVID-19 while reducing a source of IL-6 production so as to reduce the risk of cytokine storm. No actually therapeutic data, either in humans or preclinical animal models to validate such a hypothesis have been provided. Further, applicant has broadened such a hypothesis to include all possible viral infections rather than just SARS-CoV-2 as was used in identifying a possible link between TLR2, TLR7, and sensing of the SARS-CoV-2 virus.
While IL-6 can be an important components of a cytokine storm, it is known in the art that IL-6 can be protective in viral infections. For example, Lauder et al. disclose that IL-6 plays an essential role in orchestrating anti-influenza immunity through its ability to limit inflammation, promote adaptive immune responses and prevent fatal immunopathology in a mouse disease model (see entire document, particularly the title, abstract, and figures 1-8). Similarly, IL-6 deficient mice have been reported to be unable to efficiently control vaccinia virus and vesicular stomatitis virus infections (Knopf et al., see entire document). A recombinant rabies virus that also expresses IL-6 elicited a better clearance response in mice as compared to infection by wild type rabies virus (Luo et al., see entire document). Thus, rather than being a cytokine whose expression is detrimental in a viral response (as clearly implicated by applicant’s teachings to delete TLR2, and thereby effectively eliminate IL-6 production, in the claimed and administered pDC) it is clear that in many viral infections IL-6 is crucial for resolution of the viral infection in a manner that benefits the infected patient. Again, applicant has supplied no experimental data in any system demonstrating that pDC which lack IL-6 production, such as due to a deletion of TLR2, deliver clinical benefits in an infection setting, whether SARS-CoV-2 or viral infections generically, but given animal model data showing a clear clinical benefit for IL-6 production in multiple unrelated viral infections (e.g. vaccinia is double stranded DNA, rabies is negative strand RNA, etc.) it does not appear to be predictable if the claimed administration methods will deliver benefits to the patient.
As previously stated, applicant has claimed that their methods and products treat as well as “prevent” viral infections or complications arising therefrom. The specification does not appear to define “prevention” but page 14 of the specification does disclose the distinction between therapeutic (already infected) and prophylactic (not yet infected) administration, and provides the following guidance: “Also provided herein is a method of prevention or treatment of disease or condition in a subject, which method comprises administering a pDC or composition to the subject in a prophylactically or therapeutically effective amount.” Thus it is very clear from such guidance that “prevention” is not a timing limitation synonymous with “prophylaxis” but instead is a term of efficacy. Specifically, it appears that “treatment” means that the patient gets some amount better while “prevention” means they never have any symptoms whatsoever. Given the conflicting data in the scientific literature conceding the desirability for IL-6 production in a viral infection, and the total lack of experimental data in the instant specification concerning the ability of the claimed pDC to show clinical benefit in any system, it does not appear reasonable that artisans would expect the instant claimed methods and cells to “prevent” anything at all. Note that the only use for the claimed pDC in the specification appears to be for administration in a viral disease setting. Thus, if the methods are not reasonably enabled, the cells used in such a method are also not enabled because even if they can be made they cannot reasonably be used.
Therefore, in view of the brdath of the claims, the teachings of the prior art, and the guidance and direction of the instant specification, artisans would be unable to make and use the full extent of what has been claimed without first conducting additional unpredictable basic science research and experimentation,
Claim Rejections - 35 USC § 102
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 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.
Claims 1-3 and 14-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jakobsen et al. (WO 2018/206577) as evidenced by Zheng et al.
Jakobsen et al. disclose methods of producing plasmacytoid dendritic cells (pDC) from hematopoietic stem cell progenitors using cell culture conditions including cytokines and growth factors to differentiate HSPC into precursor pDC followed by maturation to fully differentiated pDC (see entire document, particularly the title, abstract, claims, and pages 3-5). It is further disclosed that such cells are to be genetically modified using techniques including electroporation and gene knockouts, and that they are suitable for use as a vaccine for infectious diseases, including viral diseases (ibid, pages 15, 23, 25, 26, 28, 31, and example 3). Notably, Jakobsen et al. disclose making MyD88 knockout pDC using Crisper/Cas9 in working example 3, and as evidenced by Zheng et al., MyD88 is necessary for the release of inflammatory cytokines including IL6 in response to SARS-CoV-2 and thus the cells generated by Jakobsen et al. are necessarily deficient in IL-6 production (see particularly page 4 of 32 of Zheng et al.). Additionally, pDC generated from HSPCs were greatly deficient in CD304 expression as compared to pDC isolated from blood (see particularly page 39 as well as figures 3 and 4). Administration of pDC in a pharmaceutical composition is explicitly disclosed (see for example page 28). Therefore the prior art anticipates that which is presently claimed.
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.
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Jakobsen et al. (WO 2018/206577) as applied to claims 1-3 and 14-16 above, and further in view of Zheng et al. and in view of CN103589727
The teachings of Jakobsen et al. have been discussed above and differ from the instant claimed invention in that they do not disclose that their pDC lack IL6 production due to alterations in TLR2 signaling, such as a genetic knockout or knockdown of TLR2.
Zheng et al. disclose that TLR2 senses the envelope protein of SARS-CoV-2 and results in the elaboration of inflammatory cytokines including IL6 (see entire document, particularly the title, abstract, and figures 2, 3, and 5). They further disclose that blocking signaling through TLR2 in vivo provided protection against COVID-19 viral pathogenesis, and indicate that inhibition of TLR2 signaling can inhibit cytokine storm and lead to more effective treatments for SARS-CoV-2 infection (see particularly figure 5 and the Discussion section).
CN103589727 discloses siRNA that inhibits TLR2 and is taught for use in human immune cells to treat viral infections (see entire English language translation, particularly the abstract and contents of the invention sections).
Therefore, it would have been obvious at the time of the invention to modify the pDC of Jakobsen et al., which are taught for administration to treat viral infections to lack expression of TLR2. This is because Zheng et al. teach that TRL2 senses the envelope protein of the SARS-CoV-2 virus and blocking signaling through TLR2 protects against the pathogenic effects of SARS-CoV-2 infection in vivo, including the release of inflammatory cytokines which include IL-6. Artisans would know that expression of TLR2 could be downregulated to treat viral infections as taught by CN103589727 and would use knockouts rather than siRNA in the pDC of Jakobsen et al. since Jakobsen disclose multiple working examples wherein various genes were disabled in pDC using Crisper/Cas9. Artisans would be motivated to do this in order to decrease the amount of IL-6 released by cells in response to the virus so as to inhibit harmful effects of infection including cytokine storm.
No claims are allowable.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
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