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 reply dated 01/09/2026 has been received.
Claim Rejections - 35 USC § 112
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 14,18,40 and 42 remain 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.
While determining whether a specification is enabling, one considered whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirement, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d at 737, 8 USPQ2d 1400, 1404 (Fed. Cir.1988)).
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raises and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The full analysis of enablement is set forth in the previous office action dated 10/10/2025. The grounds of rejection relating to the breadth of virus type in the viral infection is withdrawn in light of the amendments to claim 14. Essentially, the issue is that the specification provides in vitro data and in vivo data using mutant mice lacking the machinery (RIPK3 and DAI) for inducing cell death in viral infected cells. This cell death controls viral spread by killing the viral infected cells. The claims are drawn to a method of treating a subject (having RIPK3 and DAI expression) having an influenza A infection with vectors encoding addition RIPK3 and DAI. The evidence of record supports rescuing deficiencies in RIPK3 and DAI but does not teach expressing additional RIPK3 and DAI in normal, influenza-infected cells in vivo.
Claim 14 has been amended to recite that expression of DAI and RIPK3 activate Caspase-8 dependent apoptosis. It is noted that this is a naturally occurring process. It would occur even in the absence of exogenous DAI and RIPK3. It appears the invention may be trying to alter the balance of apoptosis and necroptosis in the favor of apoptosis to rid an infected subject of virally infected cells. According to claim 14, this would occur by the additional RIPK3 and DAI leading to increased caspase 8 activity. Data supporting this in cells having RIPK3 and DAI endogenously present is not of record. The working examples in the specification tease apart the roles of various proteins in the balance of necroptosis and apoptosis using inhibitors and mutants. It does not teach overexpressing RIPK3 and DAI in influenza-infected wild-type cells.
Some more pertinent parts of the previous rejection are presented below.
The working examples and guidance provided:
The specification discloses influenza type A virus (IAV) strains PR8 and A/HKx31 were generated by reverse genetics (e.g., example 1). ”Each of these strains induced extensive cytopathic effect (CPE) and cell death in infected wild-type MEFs within 24 hours… Similarly-infected ripk3-/- MEFs were almost completely resistant to IAV- and IBV- induced CPE and cell death” (e.g., Example 2, p. 23). “IAV replication results in assembly of a RIPK3 complex containing RIPK1, FADD and MLKL. A molecular feature of RIPK3 dependent cell death is the stimulus-driven formation of RIPK3 and RIPK1, together with FADD and MLKL”. IAV replication drives activation of RIPK3 and the kinase activity of RIPK3 was required for IAV-induced necrosome formation, while that of RIPK1 was largely dispensable (e.g., Example 2, p. 25-26). DAI is required for IAV-induced cell death, and MEFs from DAI-deficient (zbp1-/-) mice were extraordinarily resistant to death triggered by IAV. Early passage MEFs from two separately-housed zbp1-/- colonies uniformly displayed >90% viability when infected with IAV strain A/Puerto Rico/8/1934 (PR8, H1N1) while similarly-infected wild-type control MEFs manifested extensive cytopathic effect and cell death (e.g., Example 4, p. 33). DAI associates with RIPK3 and mediates both apoptosis and necroptosis in IAV-infected cells. IAV infection induced the robust association of DAI with RIPK3 and DAI was essential for recruitment of both MLKL and RIPK1 to RIPK3 (e.g., Example 4, p. 34). DAI lies upstream of RIPK3 in the pathways leading to activation of MLKL and caspase-8, and requires its RHIM to associate with RIPK3 and activate these pathways. DAI also mediates IAV-activated RIPK3-independent apoptosis, likely via recruitment of RIPK1 and activation of RIPK1-FADD-caspase-8 axis (e.g., Example 4, p. 35).
The unpredictable nature of the art:
Lenzi et al., 2014 (NCBI Bookshelf, A Service of the National Library of Medicine, National Institute of Health, Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington (DC): National Academies Press (US), pages 1-16) discuss scientific hurdles of gene transfer in vivo. Some scientific hurdles, such as the absence of efficient delivery systems, difficulty with sustained expression and host immune reactions, remain formidable challenges to the field of gene transfer. Many of the hurdles have to do with providing efficient gene delivery. For examples, the vector uptake and distribution must be tightly controlled so that expression of the vector-encoded gene remains within the therapeutic range-if the expression is too low, the functional protein product may not be produced at a high enough concentration to effectively restore the intended biochemical pathway. Transcription of the new genetic material must remain stable so that the transgene is expressed as long as necessary to treat the disease. The degree to which the vector containing the transgene is taken up in a sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the efficiency of interactions between vector and host cell receptors. The ideal vector would be cell-type specific, but the design of either non-viral or viral vectors that successfully target a specific cellular receptor has been elusive despite a great deal of effort. To date, re-engineered viral vectors are often too large, too unstable, or otherwise unable to reach the nucleus of some cell types. Non-viral gene delivery remains prohibitively inefficient for most therapeutic applications (e.g. p. 10, under “Scientific Hurdles”). For viral vectors, especially adenoviral and adeno-associated viral vectors, the exposed individuals have circulating antibodies that can interfere with transduction of closely related recombinant vectors. The control of an unanticipated immune response can be complicated by the challenge of "turning off" expression of transgene driven by constitutive, non-conditioned promoter sequence specifically designed to always be "on" (e.g. p. 11, 1st paragraph).
Importantly, post-filing, Gautam (2024, Bature,628:835-843) taught inhibition of RIPK3 prevents lung injury that occurs if necroptosis goes unchecked. Likewise, Boyd (2025, Trends in Microbiology, Month 2024, Vol. xx, No. xx, In Press) taught RIPK3 leads to necroptosis and lung injury. Thus, the claims are directed to delivering more RIPK3 which, according to Gautam and to Boyd, would lead to necroptosis. This evidences the complexity of the effects of RIPK3 on apoptosis necroptosis and the effects of influenza on the lung as well as highlights the unpredictability of how additional RIPK3 would treat influenza when both Gautam and Boyd taught RIPK3 inhibitors prevents lung injury in severe influenza. Thus, without a working example showing, in vivo, the effects of RIPK3 overexpression and how to overexpress it along with DAI, it would require undue experimentation to carry out the invention as claimed.
Applicant has shown RIPK3 and DAI are necessary for apoptosis and necroptosis that occurs when cells are infected with the flu. However, there is no support that addition of more DAI and RIPK3 would induce further apoptosis of infected cells. The cells already apoptose due to viral infection.
The Specification does not provide any working example relating to the claims. Applicant in their Remarks dated 12/16/2024 pointed to paragraphs 152, 153, 173 and 174 for support for in vivo experimentation. However, these in vivo tests involve mutant mice and do not involve the delivery of DAI or RIPK3. Given the teachings of Gautam and of Boyd (above), which support treatment of influenza with RIPK3 inhibitors as opposed to introducing more RIPK3 to infected cells, in combination with the lack of supportive working examples, and the general unpredictabilities related to gene therapy, it would have required undue experimentation for one skilled in the art before the effective filing date of the claimed invention to practice over the full scope of the invention claimed.
Applicant, in their Remarks dated 05/12/2025, provides the Nogusa (2016, of record) and Thapa (2016, of record) references. These reference support an important role for RIPK3 and DAI in necroptosis and apoptosis. These references show that the lack of RIPK3 or DAI in RIPK3 or DAI mutant cells leads to reduced death of infected cells. Exogenous DAI or RIPK3 can rescue the deficiency. These finding support a protective role for DAI and RIPK3 against influenza infection. However, they do not teach the effect of overexpressing either protein in wildtype cells. These references support the working examples and Applicant’s remarks from 12/26/2024, which are addressed above. In addition to this general deficiency, the complexity and stochastic relationship between proteins in the pathway is discussed at page 10 of Nogusa. Simple overexpression of DAI and RIPK3 would not predictably treat influenza A infection in vivo.
Applicant Remarks dated 07/25/2025 were also found not persuasive. Applicant argues the science of delivering genes to the respiratory tract using viral vectors was established and that Applicants' invention lies in the discovery of a specific DAI/RIPK3-mediated apoptosis pathway as a therapeutic target for influenza that overcomes the uncertainty in the field. Applicant's arguments and guidance in the Specification support a role for DAI/RIPK3 in apoptosis in influenza infected cells. However, it is maintained that there is no support that addition of more DAI/RIPK3 will lead to any changes in the apoptosis that naturally occurs from viral infection or that addition of more DAI/RIPK3 will have any treatment effect or effect on the level of apoptosis in infected cells.
Applicant argues in the Remarks of 01/09/2026, that the claims are now directed to specifically utilizing caspase-8 dependent apoptosis, which clears the virus without triggering inflammatory necroptosis. This fails to address the issue described above as the claims still are directed to adding addition DAI and RIPK3 in cells that already express these genes. The evidence of record supports altering the balance of apoptosis and necroptosis by use of inhibitors or mutations that disrupt the process and then rescuing the effects with exogenous protein. These experiments tease apart the pathway, highlight the complex nature of the balance of the two and show which proteins are necessary for apoptosis, necroptosis, and the appropriate balance. Reciting the effect of activating Caspase-8 appears to be an intention or theory that does not have effective support.
With regard to newly added claim 43, the claim adds that the infected cells exhibit reduced or suppressed endogenous expression of DAI, RIPK3 or both. Applicant points to paragraphs 20, 152,153,173 and 174 for support. Para 20 supports that infection activates RIPK3 and the necrosome complex. Paragraph 152 discusses the contribution of MLKL in necroptosis and FADD in apoptosis using mutant analysis. Para 153 supports increased viral spread due to the lack of cell death in ripk3-/- mice. This supports a necessary role for RIPK3 in viral elimination and death of infected cells. Paragraph 173 teaches that mice lacking DAI die from infection with paragraph 174 supporting that higher viral numbers occur in these mice. Thus, these excerpts in the specification fail to support that endogenous expression of RIPK3 and DAI occur from viral infection. If the claims intend to refer to artificially induced mutation of these genes such that the genes are lacking and the method restores this, claims should be amended accordingly.
New Matter
Claims 43 is rejected under 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention. 37 CFR 1.118 (a) states that “No amendment shall introduce new matter into the disclosure of an application after the filing date of the application”.
Claim 43 is drawn to the method of inducing apoptosis of claim 14 and adds that the infected cells exhibit reduced or suppressed endogenous expression of DAI, RIPK3 or both. Claim 43 encompasses any level and cause of reduction of RIPK3 and/or DAI. This includes a natural reduction that could occur upon viral infection or through some secondary treatemnt. The only support found in the specification is the use of RIPK3 and DAI knockout mouse mutants. Applicant points to paragraphs 20, 152,153,173 and 174 for support. Paragraph 20 supports that infection activates RIPK3 and the necrosome complex. Paragraph 152 discusses the contribution of MLKL in necroptosis and FADD in apoptosis using mutant analysis. Para 153 supports increased viral spread due to the lack of cell death in ripk3-/- mice. This supports a necessary role for RIPK3 in viral elimination and death of infected cells. Paragraph 173 teaches that mice lacking DAI die from infection with paragraph 174 supporting that higher viral numbers occur in these mice. Thus, these excerpts in the specification fail to support that endogenous expression of RIPK3 and DAI occur from viral infection. If the claims intend to refer to artificially induced mutation of these genes such that the genes are lacking and the method restores this, claims should be amended accordingly.
The specification provides no implicit or explicit support for the context of the breadth of expression of reduced or suppressed endogenous expression of DAI, RIPK3 or both. The specification has only provided support for expression of the DNA construct in the context of the claimed transgenic mouse. Applicants are reminded that it is their burden to show where the specification supports any amendments to the claims. See 37 CFR 1.121 (b)(2)(iii), the MPEP 714.02, 3rd paragraph, last sentence and also the MPEP 2163.07, last sentence.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure [or point to case law supporting incorporation of such a limitation as in the instant case]” (emphasis added).
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 VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632