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 .
Application Status
This action is written in response to applicant’s correspondence received June 16, 2026.
Claims 9, 10, 12-17, 30, 31, 33-38 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim in the reply filed on 25 Sept, 2025. Claims 2, 5, 13-18, 28, and 34-38 are cancelled. Accordingly, claims 1, 3-4, 6-8, 11, 18-27, 29, and 32 are under consideration.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Priority
Acknowledgment is made of applicant's claim for priority based on a US Provisional Application No. 63/215,882 filed on 28 June, 2021.
Withdrawn - Drawings
In view of the concurrent submission of drawing substitute sheets, the objections to the drawings have been withdrawn.
Withdrawn Claim Rejections - 35 USC § 101
Instant amended claims 1 and 25 recites “administering an effective amount of an inhibitory nucleic acid molecule that inhibits p97 in the subject, wherein the inhibitory nucleic acid molecule reduces the expression level of a coronavirus viral protein and/or viral titer in the subject after the administration”. Claims 1 and 25 are particular from a claim that merely recites “administering a suitable medication” (MPEP 2106.04(d)(2)(a)). As Applicant argues, “the claim recites a particular disease, a particular therapeutic mechanism, and a particular therapeutic outcome” (pg. 7, para. 2). This argument has been fully considered and the amendments to the claims 1 and 25 changed the scope of the claim, particularly the administration step. The amended administration step integrates an abstract idea into a specific antiviral intervention that achieves a defined antiviral result in a treated subject. Accordingly, the rejection of claims 1, 3-4, 6-8, 11, 19, 21, 25-27, 29, and 32 under 35 USC 101 is withdrawn.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 23 and 24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1
Claim 23 is directed to a method of identifying a subject having a coronavirus infection…comprising”. Thus, the claimed invention is directed to a process, which is one of the statutory categories of invention.
Step 2A, Prong 1
Claim 23 recites “identifying” and “detecting”, which is abstract mental concept that belong to numerated group (c) of the Abstract Idea Groupings described in MPEP § 2106.04(a)(2): Mental processes - concepts that performed in the human mind (including an observation, evaluation, judgement, opinion). Thus, the claims recite a judicial exception.
Claim 24 is dependent claim of claim 23 and thus recite the judicial exception identified for corresponding independent claims.
Step 2A, Prong 2
Regarding claim 23, recitation of “detecting at least one of: a level of a product or expression of a gene…” is an additional mental analysis step which cannot integrate the judicial exception into a practical application. The amended claim limitation of “by immunoblotting and/or quantitative polymerase chain reaction” merely adds insignificant extra-solution activity to the judicial exception as these limitations are mere data gathering in conjunction with an abstract idea (see MPEP 2106.05(g)).
Further, there are no additional elements that reflect an improvement within the technical field; there are no additional elements that apply the natural correction/phenomena judicial exception to a particular treatment or which utilize a particular machine; there are no additional elements that effect a transformation; and, there are no additional elements that apply the judicial exception in some other meaningful way beyond generally linking it to a field, namely, viral infection.
While dependent claim 24 recites additional elements directed to gene expression in a subject having a coronavirus infection, they still do not integrate the judicial exception into a practical application.
Step 2B
Although claim 23 recites the amended claim limitation, Gallagher et al (Immunoblotting and Immunodetection; Current Protocols in Molecular Biology, 2008, unit 10.8.1-10.8.28) disclose immunoblotting is routinely used to detect of the presence or absence and amount of a specific protein during gene expression, to track markers and reporter genes in organisms to get a complete picture of transcription and translation (Table 10.08.3). Thus, this additional element is well-understood, routine, conventional activity that is not sufficient to amount to significantly more than the judicial exception (see MPEP 2106.05(d)).
Response to Arguments
Applicant argues that amended claim 23 recites methos of identifying a subject as having a coronavirus infection by detecting a level or product or expression of a gene, the detection is done with laboratory techniques (emphasis added) (pg. 8, para. 3). Applicant’s arguments have been fully considered but they are not persuasive because as stated above, detection by immunoblotting and/or quantitative polymerase chain reaction is mere data gathering in conjunction with an abstract idea, and these additional elements are well-understood, routine, conventional activity, (i.e., laboratory techniques pointed by Applicant) that do not amount to significantly more than the judicial exception.
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.
Claims 24 and 29 are 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 claims 24 and 29, the recitation of a relative term “differently" renders the claims indefinite because these terms are not defined by the claim and the specification does not provide a standard for ascertaining the requisite degree. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification does not define this relative term nor it teaches the differences between proteins expressed by a subject with and without coronavirus infection, such as expression levels, folding structures, amino acid sequences, and size.
Claim Rejections - 35 USC § 112 – Written Description
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, 3-4, 6-8, 11, 19, 21, 25-27, 29, and 32 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.
MPEP 2163.II.A.3(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or couple with a known or disclosed correlation between structure and function, and the method of making the claimed invention”. MPEP § 2163 further states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. Claims 1 and 25 are drawn to a method of treating coronavirus infection comprising administering an inhibitory nucleic acid molecule that (i) inhibits p97, and (ii) reduces the expression level of a coronavirus viral protein and/or viral titer. The claimed inhibitory nucleic acid molecule encompasses a broad genus defined solely by two recited functional properties, rather than by any common structural features or identifying sequence characteristics. Claim 11 also solely narrows the breadth of the claim to encompass a genus of shRNA defined by the two functional properties without structural features. Because the genus is claimed in terms of the results achieved, structural features common to the claimed genus must be adequately described to demonstrate that Applicant was in possession of the full scope of inhibitory nucleic acid molecules capable of achieving claimed functions.
The specification teaches that inhibition of p97 could be achieved using a nucleic acid molecule, an antagonist, a genetic tool, and a small molecule ([0042]-[0062]). The specification further teaches inhibition of p97 in vitro in two lung cancer cell lines A549 and H1299 using a shRNA SEQ ID NO:1 (Examples 1-4). However, SEQ ID NO:1 is the only shRNA sequence disclosed by Applicant with no additional sequence variants, no structure-function guidance, no loop nucleotide sequence. Therefore, this shRNA is characterized as a siRNA. Accordingly, the specification fails to disclose the complete structure of the only embodiment claimed to be shRNA, relevant identifying characteristics of the claimed genus, representative number of species, and correlation between structure and claimed function.
The state of the art teaches two types of inhibitors for p97 for viral therapies: siRNA and small molecule. In regards to inhibitory nucleic acid molecules, Phongphaew et al (Virus Res, 2017, 228: 114-123) teaches inhibition of p97 using siRNA requires rational design of siRNA complementary to various conserved regions of p97 and possible screening of effective siRNA as results demonstrated that one of the designed siRNA failed to inhibit p97 in West Nile virus-infected cells (pg. 117, section 3.2). Similarly, Wong et al (J Virol., 2015, 89: 11116-11128) teaches only one of the “custom-designed siRNAs” successfully inhibited p97 in HCoV-229E-infected cells (pg. 11120, right-column), which is only one species within the claimed genus of coronavirus infection.
In regards to shRNA, while Baroy et al (Mol Biotechnol (2010) 45:116-120) teaches strategies to design shRNAs from siRNA sequences, it was demonstrated that only 19 out of the 25 shRNA constructs were efficient in reducing target expression (Abstract), indicating that designing shRNA constructs directly from siRNA is unpredictable. Further, the state of the art does not recognize relevant identifying characteristics of shRNAs capable of inhibiting p97 and reducing expression level of a coronavirus viral protein as prior art studies center on siRNA.
Together, the art establishes that inhibition of p97 by siRNA cannot be predicted solely from sequence complementary, and effective species must be identified through screening and validation.
The dependent claims 3-4, 6-8, 11, 19, 21, 25-27, 29, and 32 recite additional limitations to the method of claim 1 and the method of claim 25, such as shRNA inhibitory nucleic acid molecule, viral infection type, viral proteins, and results of the inhibition of p97. Therefore, the dependent claims are also rejected for depending from a rejected claim and failing to remedy the lack of written description therein.
Based on the preponderance of the evidence, including the relevant teachings of the specification, the absence of working examples, and the state of prior art including the knowledge of nucleic acid molecules that inhibit p97 and reduce expression level of a coronavirus viral protein, Applicant was not in possession of the full scope of nucleic acid inhibitors of p97, including the genus of shRNA recited in the claims.
Response to Arguments
Applicant argues that “the specification discloses a specific p97-targeting shRNA sequence in the examples” (pg. 10, para. 2), “the Examples confirm possession of the claimed subject matter through working examples” (pg. 10, para. 4), and “the specification specifically describes “an inhibitory nucleic acid molecule that inhibits p97” through teachings of shRNA-mediated p97 depletion, demonstrates antiviral effects from that inhibitory nucleic acid approach, and links that approach to the disclosed cell-cycle-related biomarker changes during HCoV infection” (pg. 11, para. 1).
Applicant’s arguments have been fully considered but they are not persuasive because as stated above, the only embodiment SEQ ID NO: 1 disclosed in the specification is characterized as a siRNA, not shRNA as described. The specification fails to disclose the loop nucleotide sequence, complete structure, or any relevant functional characteristics alone or coupled with a disclosed correlation between structure and function (i.e., inhibits p97 and reduces expression level of a coronavirus protein and/or viral titer recited in the claims). Further, the disclosure of one embodiment is not representative of the claimed genus when the disclosure lacks additional sequence variants. In addition, the state of the art establishes inhibition of p97 via nucleic acid molecules is unpredictable as functional activity of the nucleic acid molecules is trial and error. Accordingly, the claims lack written description support for the claimed genus of inhibitory nucleic acid molecules.
Claim Rejections - 35 USC § 112 - Enablement
Claims 1, 3-4, 6-8, 11, 19, 21, 25-27, 29, and 32 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.
The specification does not reasonably provide enablement for the use of a method to treat a coronavirus infection in a subject by administering a nucleic acid molecule that inhibits p97. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with the claims.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics., 8 USPQ2d 1217 (Fed. Cir. 1988)). Whether undue
experimentation is needed is not based upon a single factor but rather is a conclusion reached by weighing many factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of Claims
With respect to claim breadth, the standard under 35 U.S.C. §112(a) entails determining what the claims recite and what claims mean as a whole. The nature of the invention is directed to a method of treating Coronavirus infection in a subject by administering a nucleic acid molecule that inhibits p97, leading to reduction of Coronavirus viral titer, cytopathic effects, and replication, as well as reduction of Coronavirus infection or a symptom thereof. Accordingly, the claims require three key structures: 1) a nucleic acid molecule that inhibits p97, 2) inhibition of p97 affects Coronavirus replication, and 3) administration in vivo, to a subject. The claims broadly recite any nucleic acid inhibitors of p97 and administered to any subject human or non-human mammal, as defined in the specification (see [0028]). Claims 11 and 32 also encompass a broad genus of shRNA inhibitors of p97.
Guidance of the Specification
The specification does not teach how to make and use additional species across the genus of shRNA that inhibits p97. Further, the specification does not enable any person skilled in the art to which it pertains (i.e. administering an shRNA that inhibits p97 in a subject to treat a coronavirus infection) to make and/or use the invention commensurate in scope with the claims. There is a lack of adequate guidance from the specification or prior art with regard to the actual method comprising inhibitory shRNA or any inhibitory nucleic acid molecule of p97 capable of treating coronavirus infection in a subject.
Regarding route of administration, the specification teaches “inhibitors of p97 can be
administered by any suitable route of administration”, including oral administration, rectum administration, transdermal administration, intranasal administration, inhalation, by injection or in the form of a tablet, capsule, patch or a drink ([0068])
Regarding treatment dosage, the specification teaches i) an “effective amount” of an agent to administer depends “upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, a physical or veterinarian will decide the appropriate amount and dosage regime” ([0032], ii) doses of p97 inhibitors can be readily determined for a given subject based on their body mass, disease type and state, and desired aggressiveness of treatment” ([0067]), and iii) “p97 inhibiting agent is administered to the subject until a coronavirus infection, or a symptom thereof in the subject is reduced” ([0061]).
These general statements do not provide any specific guidance regarding how to administer a nucleic acid molecule that inhibits p97 to a subject.
Regarding methods of treating a coronavirus infection, the specification teaches “an ATP-competitor can be used to inhibit the enzyme activity of p97” ([0055]), “the coronavirus infection is caused by the members of the Coronavirinae subfamily of viruses” [0056], “identifying a subject who would benefit from inhibiting p97” ([0058]). The specification further teaches generation of stable H1299 cell lines expressing one shRNA SEQ ID NO:1 for inhibition of p97 in vitro upon infection with two viruses HCoV-229E and HCoV-OC43 (Examples 1-4), and proteomic analysis of viral proteins post-inhibition. However, there is no specific guidance on how to practice the present invention.
The specification does not provide the following evidence:
i) any representative working examples of in vivo treatment of coronavirus infection using shRNA, including animal or human data showing antiviral efficacy of any shRNA sequences
ii) guidance on selecting shRNA inhibitors of p97 that will reliably reduce viral load in vivo
iii) disclosure of delivery systems, formulations, and routes of administration for effective shRNA expression in respiratory tissues in a subject considering host immune responses. Disclosure could include AAV vector serotypes, viral titers, nanoparticle or plasmid compositions, administration method and frequency.
vi) disclosure of dosing ranges or pharmacokinetic data that would allow a person ordinary skill in the art to make and/or use the claimed method
Thus, such disclosure does not teach a method of treating a coronavirus infection by administering the claimed genus of shRNA inhibitors of p97, and let alone an agent that promotes inhibition of p97. The working embodiments of reducing viral titers of two coronavirus species do not support the claimed scope of reducing a viral infection. Lastly, the working embodiments of treatment in two lung cancer cell lines do not support the claimed scope of treatment in a subject.
State of the Art
At the time of filing, the state of the art relating to p97 inhibition-based antiviral therapies demonstrated that p97 inactivation could suppress virus at the cellular level.
Arita et al (J. Virol., 2012, 86, 10: 5541-5553) demonstrated siRNA-mediated inhibition of valosin-containing protein (referred as p97 in the instant case) host factor successfully suppressed replication of poliovirus in vitro because ATPase activity of p97 is essential for viral replication (Fig. 1A, Table S1, and pg. 5543). Arita further teaches that knockdown of p97 did not suppress replication of other virus in the same genus or family, and a mutant poliovirus, which has a secretion inhibition-negative phenotype, resisted p97 knockdown compared to wild-type poliovirus(pg. 5542, left-column, second paragraph). Thus, prior art does not recognize inhibition of p97 in cells and suppressed replication of one viral strain could predictably yield similar outcomes in cells-infected by a different viral strain from the same genus or family.
Lin et al (PloS Pathog., 2017, 15, 5: e1006329) also demonstrated siRNA-mediated inhibition of p97 successfully suppressed replication of human cytomegalovirus in vitro because ATPase activity of p97 is essential for the expression of virus gene IE2 (Fig. 2 and 4, pg.3-11). Lin further teaches a small molecule inhibitor of p97, NMS-873, is also a potent antiviral for human cytomegalovirus (Fig. 10, pg. 13) but it shows additional off target effects compared to siRNA-mediated knockdown of p97.
Phongphaew et al (Virus Res, 2017, 228: 114-123) also demonstrated siRNA-mediated inhibition of p97 successfully suppressed replication of West Nile virus in vitro by reducing expression levels of virus E protein (Fig. 2, pg. 117). Phongphaew further teaches that only two of the three siRNAs targeting three different regions of the p97 gene successfully knockdown endogenous p97 (pg. 117, section 3.2), indicating that rational design and experimental optimizations of siRNAs are required to achieve effective inhibition of p97.
As of the filling date, prior art supports that p97 plays an important role in replication of one coronavirus species but inhibition of p97 to treat coronavirus remains unpredictable. Wong et al (J Virol., 2015, 89: 11116-11128) applied siRNA screening and identified p97 is also essential for human coronavirus HCoV-229E replication as loss of p97 inhibits nucleocapsid N protein in vitro, reduced viral titers, cytopathic effects, and rate of viral replication (Fig 3, pg. 11120-11121). However, “the exact mechanism by which p97 facilitates N protein degradation is also currently unclear” (pg. 11126, col. 1 para. 1). Wong also teaches custom-designed siRNAs are required for effective inhibition of p97 (pg. 11120, right-column). Wong further discloses coronaviruses have a propensity for host switching due to the diverse range of species that they infect (pg. 11116, col. 1, para. 2) and more work is obviously required to sort out the precise function(s) of p97 and its requirement for infection by coronavirus and other viruses (pg. 11126, col. 1, para. 4).
Separately, Kristijan et al (WO 2021/023973 A1; Published Date: 11 Feb 2021; Filed Date: 30 Jul 2020) has demonstrated that the siRNA-mediated depletion of p97 (using the same sequence as the instant SEQ ID NO: 1 disclosed in specification [0067]) could be used in vitro to indirectly regulate expression topoisomerase 1 (Figure 1, pg. 27 “sip97#3), which serves as a biomarker for metastatic colorectal cancer therapy (pg. 1).
Further, The Food and Drug Administration (hereinafter, FDA) (Antiviral Product Development – Conducting and Submitting Virology Studies to the Agency, Guidance for Industry, Center for Drug Evaluation and Research; Published Date: June 2006; Content current as of: 24 Apr 2020) recommends preclinical development plans for antiviral products that sponsors should generate before moving into preclinical stage studies for antiviral products, including coronavirus. The FDA guidance makes it clear that in vitro studies alone are not sufficient to support clinical development (see section V. “Virology study reports”), and regulators highlight the following information should be included on nonclinical studies:
“(i.e., mechanism of action, antiviral activity in vitro, cytotoxicity and therapeutic indexes, effects of serum protein binding on antiviral activity…in vitro selection of resistant viruses to the investigational product, the phenotypic and genotypic characterization of resistant viruses, cross-resistance before initiation of clinical studies” (pg. 3)
Considering the guidance from the FDA, it can be concluded that that extrapolating from in vitro inhibition of p97 to effective and safe treatment of viral infection in a subject is not routine or predictable because transition from in vitro to in vivo efficacy and safety is highly uncertain.
In summary, as of the filling date, there is no prior art disclosing any successful in vivo therapeutic treatment of viral infection using any agents that promotes inhibition of p97. The state of the art did not provide guidance on delivery systems, dosing regimens, expression control, or safety considerations that are necessary to achieve effective inhibition of p97 in a subject with coronavirus infection without substantial and unpredictable experimentation.
Experimentation Required
For example, it would be necessary for one of ordinary skill in the art to conduct the following experimentation in order to practice the claimed invention:
1) designing and screening inhibitors that effectively inhibit p97 in a subject (see teachings of Phongphaew and Wong regarding different siRNAs showing various degree of inhibitions)
2) developing a suitable delivery system, such as nanoparticles, viral vectors, and chemical modifications, capable of transporting the inhibitor to relevant tissues (e.g., lung tissues for coronavirus) in a subject
3) determining in vivo dosing, pharmacokinetics, formulations, and drug stability for therapeutic inhibition of p97 in a subject
4) evaluating therapeutic efficacy and safety in a subject, including reduction of viral load, mitigation of infection symptoms, host-immune response, and off-target effects (see teachings of Lin and Wang)
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the concluded that an unreasonable amount experimentation would be required to make and use the invention as claimed.
Response to Arguments
Applicant argues that “the specification teaches shRNA as a p97 inhibitor…and provides an operative experimental framework showing the antiviral effect of p97 knockdown in HCoV-229E and HCoV-OC43 infection models…Example 3 further shows that p97 depletion reduced viral protein abundance in infected cells” (pg. 12, para. 3).
Applicant’s arguments have been fully considered but they are not persuasive. While the disclosed experiments may demonstrate that p97 knockdown reduces viral protein abundance in cells-infected by HCoV-229E and HCoV-OC43, the claims are not limited to these embodiments, but instead encompass treatment of coronavirus infection broadly. The state of the art indicates unpredictability in extending antiviral efficacy across different viral species or strains, see teachings of Arita et al (cited supra). Prior art also recognizes that coronavirus comprises a diverse family of viruses capable of infecting multiple host species and undergoing “interspecies jumping” as taught by Wong et al (cited supra), resulting in genetic diversity among coronaviruses. Accordingly, the limited working examples involving two human coronaviruses do not reasonably establish that the single embodiment of shRNA-targeting p97 would be effective for the full scope of the claimed method. A person ordinary skilled in the art would therefore be required to identify and verify therapeutic activity across additional coronavirus species or strains through further experimentation.
Applicant argues that “some optimization may be required in adapting the disclosed shRNA embodiment for therapeutic use in a subject, but does not amount to undue experimentation” (pg. 13, para. 2).
Applicant’s arguments have been fully considered but they are not persuasive because the state of the art demonstrates that effective siRNA-mediated inhibition of p97 is virus-specific, with custom-designed siRNA being generated and screened for individual viruses, including poliovirus, cytomegalovirus, and human coronavirus HCoV229E to achieve inhibition of viral replication in infected cells. The prior art does not suggest that a single p97-targeting shRNA would be broadly effective across different viral infections or coronavirus species, but instead indicates that rational design and validation are required for each viral infection. In addition, the prior art is limited to in vitro studies and does not provide guidance for translating such siRNA into effective therapeutics in a subject. As discussed in previous Office Action mailed on Dec 23, 2025 and in instant Office Action, successful in vivo application requires additional considerations and undue experimentation. Accordingly, the transition from the disclosed single in vitro shRNA embodiment to the full scope of the claimed invention would require more than routine optimization and instead would necessitate undue experimentation.
Claim Rejections - 35 USC § 112 - Enablement
Claims 23-29, and 32 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.
Claims 23 and 24 are directed to a method to identify a subject having coronavirus infection by detection of biomarkers CDC20, CDC27, PSMD14, and PSMB3. This method is also recited as one of the steps in the method of claim 25. The specification does not reasonably provide enablement for the use of a method to identify a subject having coronavirus infection by detection of listed biomarkers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with the claims.
The most relevant factors in a test for enablement are below:
Nature of the Invention and Breadth of Claims
The claims are directed to a method of identifying a subject having coronavirus infection by detecting the level of one of the biomarkers CDC20, CDC27, PSM14, or PSMB3 in a subject. Claim 25 further recites comparing the detected levels to indicate the presence of coronavirus infection.
Guidance of the Specification
The specification does not enable any person skilled in the art to which it pertains (i.e. detecting the level of a product or expression of a gene from the listed biomarkers) to make and/or use the invention commensurate in scope with the claims. There is a lack of adequate guidance from the specification or prior art with regard to the actual method comprising detecting expression of these biomarkers in a subject.
Regarding detection of biomarkers, the specification teaches the use of TMT-label proteomics for analyzing protein expression changes before and after coronavirus infection in two lung cancer cell lines, followed by proteomic data processing ([0072]-[0075]). The specification further teaches CDC27, CDC20, PSMD14, and PSMB3 expression level increases or decreases by only upon depletion of p97 ([0070]). Experimental data supported this statement wherein two proteasome related proteins, PSMD14 and PSMB3, and two components of the anaphase promoting complex or cyclosome (APC/C), CDC27 and CDC20 had different expression levels in coronavirus infected-cells that were treated with p97 inhibitor versus untreated cells (Fig. 3F). There is no teaching of how to adapt these in vitro proteomic methods for detecting of biomarkers in a subject, or how to obtain a biological sample from a subject to then apply these methods for detection of biomarkers. The specification does not disclose any steps for detecting these biomarkers in the absence of p97 depletion in vitro, let alone in a subject.
State of the Art
As of the filling date, Auwul et al (Briefings in Bioinformatics, 2021, 22(5): 1-13) teaches analysis of RNA-Sequencing datasets of SARS-CoV-2 showed that CDC20 is a key gene module and hub target involved in COVID-19 (Abstract), indicating that it could be potential biomarker for detection of presence of coronavirus in cells. Further, the state of the art teaches standard protocols for detecting biomarker expressions levels in cells, such as Western Blotting for protein detection, RT-qPCR or RNA-seq for gene expression detection, and high-throughput proteomics for relative quantification of overall protein expressions.
While some differentially expressed genes associated with coronavirus and methods for expression analysis are known, art does not teach a routine method for detecting these biomarkers in a subject for the purpose of diagnosing coronavirus infection. Thus, undue experimentation is required to practice the claimed method.
Experimentation Required
For example, it would be necessary for one of ordinary skill in the art to conduct the following experimentation in order to practice the claimed invention:
i) designing and validating assays capable of detecting expression of these biomarkers in biological samples from subjects
ii) optimization of assays including biological sample type, assay sensitivity, assay format, appropriate controls for comparison of expression levels
iii) establishing baseline expression levels in subjects not infected with coronavirus, and defining criteria that can reliably determine the presence of coronavirus
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the concluded that an unreasonable amount experimentation would be required to make and use the invention as claimed.
Conclusion
No claims are allowable.
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.
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/QIWEN SU-TOBON/
Examiner
Art Unit 1636
/NEIL P HAMMELL/ Supervisory Patent Examiner, Art Unit 1636
Prosecution Insights