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
The amendment filed on 8/05/2026 is acknowledged and has been entered. Claims 1-20 are currently pending and under consideration.
Claim Interpretation
In response to the Examiners claim interpretation of Claim 1, Applicants assert that claim 1 expressly recites prevention of injury caused by at least one virus. Applicants contend that similar claim limitations are present in claim 11. In view of Applicants statements, the examiner is interpreting claims 1 and 11 as having at least one virus.
The examiner claims interpretation of Claims 7, 10, 17 and 20 which recite SEQ ID NO #’s to identify specific proteins is maintained. In particular, these proteins do not appear to be involved in the active step of administration, but appear to refer to “natural” portions of or consequences of COVID-19 infection. As such, if one is infected with COVID-19, it would appear that the patient would necessarily have the recited proteins.
Rejections Withdrawn based on Applicants response to the Claim interpretation of claims 1 and 11:
The rejection of Claim(s) 1, 3-8, 11 and 13-18 under 35 U.S.C. 102(a)(1) as being anticipated by Tianjin University of Traditional Chinese Medicine (CN113262222A, 2021-08-17, Google translation provided) referred to herein as Tianjin.
The rejection Claim(s) 1, 3-8, 11 and 13-18 under 35 U.S.C. 102(a)(1) as being anticipated by Feige et al. (WO2021/004922A1, 2021-01-14).
The rejection of Claim(s) 2 and 12 under 35 U.S.C. 103 as being unpatentable over Feige et al. (WO2021/004922A1, 2021-01-14), as applied above to claims 1, 3-8, 11 and 13-18 above, in view of Ilavelnil et al. (Phytomedicine 2014; 21: 758-765).
Objections/Rejections maintained:
Claim Objections
Claim 3 remains objected to because of the following informalities:
Claim 3 has been amended to recite “is comprises”. It is suggested that Applicants amend the claim to delete “comprises”. Appropriate correction is required.
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.
The factual inquiries 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.
Claim(s) 1-8 and 11-18 remain rejected under 35 U.S.C. 103 as being unpatentable over Feige et al. (WO2021/004922A1, 2021-01-14) in view of Zheng et al. (Trends in Immunology 2022; 43(4):283-295). Note: This rejection assumes that the patient population has a virus.
Feige et al. teach compositions comprising trigonelline and a method of treating mitochondria-related diseases or a condition associated with altered mitochondria function in an individual in need thereof comprising administering said composition comprising trigonelline, wherein trigonelline increases intracellular levels of NAD+ in cells and tissues (abstract and paragraph 001)). With regards to the mitochondria-related diseases or a condition, Feige et al. teach that these diseases or condition include, but is not limited to, obesity, overweight, diabetes, hypertension, cardiovascular disease and HIV infection stroke (paragraph 00101). Moreover, Feige et al. teach that, for humans, amounts of trigonelline in the composition range from 1.0mg to 10.0g/kg of body weight.
Feige et al do not specifically teach that the condition associated with altered mitochondria function and in need of an increase in NAD+ is COVID-19.
Zheng et al. teach NAD+, as an emerging regulator of immune responses during viral infections, may be a promising therapeutic target for coronavirus disease 2019 (COVID-19) (abstract). Specifically, Zheng et al. teach that NAD+ metabolism appears to be linked to infections of SARS-CoC-2 and other viruses via multiple lines of evidence, epidemiological and mechanistic (page 292, concluding remarks). Zheng et al. further teach that NAD+ concentrations are also low in certain comorbidities associated with Covid-19 severity including insulin resistance and diabetes mellitus. Moreover, in humans, Zheng et al. teach that metabolic syndrome and obesity have been associated with low NAD+ concentrations in adipose tissue (page 284, Comorbidities).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by Feige et al. to include patients suffering from Covid with comorbidities, such as diabetes or obesity in view of the teachings of Zheng. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Feige et al. teach using trigonelline for increasing NAD+ in cells and tissues; and
-Zheng et al. suggests that low concentrations of NAD+ are associated with COVID-19 and comorbidities associated with COVID-19 including diabetes and obesity.
In response to this rejection, Applicants contend that Feige is directed to the use of trigonelline for increasing intracellular NAD+ biosynthesis and treating or preventing mitochondrial-related diseases or conditions associated with altered mitochondrial function, but does not disclose SARS-CoV-2, a SARS-CoV-2 spike protein, a viral cause of injury, spike protein exacerbated lipotoxicity, enhanced lipid deposition on a cell membrane caused by a SARS-CoV-2 spike protein, or treatment of both endothelial cells and cardiomycytes in the context of virus-induced heart injury. Thus, Applicants contend that the Office Action’s anticipation appears to rely on the premise that administering the same compound to a broadly overlapping patient population and that the claimed attenuation of spike-protein exacerbated lipotoxicity and mitochondrial dysfunction would therefore be an inherent property. However, Applicants contend that the fact that trigonelline may have beneficial effects in mitochondrial related diseases does not necessarily mean that Freige method attenuates enhanced lipid deposition on a cell membrane caused by SARS-CoV-2 spike protein, not that Freige necessarily treats injury caused by at least one virus.
Regarding Zheng, Applicants contend that Zheng is an opinion article discussing NAD+ in COVID-19 and viral infections suggesting that interventions that boost NAD+ concentrations might promote antiviral defense and suppress uncontrolled inflammation and states that NAD+ may be a promising therapeutic target for COVID-19 and associations between low NAD+ concentrations and risk factors for poor COVID-19 outcomes, including aging, diabetes, obesity and cardiovascular disease. Thus, Applicants contend that the cited combination fails to teach or suggest the amended claim limitation requiring attenuation of spike-protein exacerbated lipotoxicity including enhanced lipid deposition on a cell membrane caused by a sever acute respiratory syndrome coronavirus 2 spike protein.
These arguments have been carefully considered, but are not found persuasive.
Regarding Applicants’ arguments pertaining to Feige, the Examiner acknowledges that the independent claims have been amended to include limitations limiting what trigonelline attenuates upon administration. However, the Examiner recognizes that this does not appear to further define the broad patient population. Moreover, "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Regarding the arguments pertaining to the combination, the Examiner recognizes that the combination of the references teaches administering trigonelline, which has been shown to increase NAD+, to a patient suffering from COVID-19, wherein low concentrations of NAD+ are associated with COVID-19 and comorbidities associated with COVID-19 including diabetes and obesity. Thus, while the examiner acknowledges and does not dispute Applicants contention that there is no teaching of the attenuation of spike-protein exacerbated lipotoxicity including enhanced lipid deposition on a cell membrane caused by a sever acute respiratory syndrome coronavirus 2 spike protein by the combination. The Examiner recognizes that
“The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006)” See MPEP 2144(IV).
Moreover, the Examiner recognizes that the attenuation of spike-protein exacerbated lipotoxicity including enhanced lipid deposition on a cell membrane caused by a sever acute respiratory syndrome coronavirus 2 spike protein appears to be directly related to administration of trigonelline. In other words, it does not appear Applicants are doing anything different to trigonelline for it to have this result. Thus, it appears that this is a property of the compound when administered to the patient population, e.g. a patient having COVID-19. Applicants are reminded that "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). See MPEP 2112 (I) combination concerns trigonelline attenuation of adipocyte differentiation and lipid accumulation in 3T3-L1 adipocytes, but does not teach or suggest SARS-CoV-2, a SARS-CoV-2 spike protein, a viral cause of injury, spike protein exacerbated lipotoxicity, enhanced lipid deposition on a cell membrane caused by a SARS-CoV-2 spike protein, or treatment of both endothelial cells and cardiomycytes in the context of virus-induced heart injury. Accordingly, Applicants contend that the cited combination suggests that trigonelline may be of interest in obesity, metabolic disease or mitochondrial-related conditions, which is materially different than the amended claims requiring preventing an injury caused by at least one virus.
Lastly, Applicants assert that the Office Action has not established a reasonable expectation of success since Zeng expressly presents NAD+ modulation for COVID-19 as an emerging and investigational therapeutic area, noting that further research is warranted to better understand the mechanistic role and clinical utility of NAD+ interventions.
These arguments have been carefully considered but are not found persuasive.
In response to Applicants’ arguments, the Examiner recognizes that Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’") (see MPEP 2143.02(I)).
In particular, Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976) (see MPEP 2143.02 (II).
In the instant case, the Examiner recognizes that Zheng reviews the epidemiological and mechanistic data supporting the role of NAD+ in modulating the outcomes of viral infection, with a focus on SARS-CoV and SARS-CoV-2. Thus, while Applicants contend that Zheng is an opinion article, Zheng is clearly providing epidemiological and mechanistic data to supporting the role of NAD+ in modulating the outcomes of viral infections. Therefore, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by Feige et al. to include patients suffering from Covid with comorbidities, such as diabetes or obesity in view of the teachings of Zheng. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Feige et al. teach using trigonelline for increasing NAD+ in cells and tissues; and
-Zheng et al. suggests that low concentrations of NAD+ are associated with COVID-19 and comorbidities associated with COVID-19 including diabetes and obesity.
The rejection of Claim(s) 9-10 and 19-20 remain rejected under 35 U.S.C. 103 as being unpatentable over Feige et al. (WO2021/004922A1, 2021-01-14) in view of Zheng et al. (Trends in Immunology 2022; 43(4):283-295), as applied above to claims 1-8 and 11-18, in further view of Selvaraj et al. (F1000Research 2021; 10:127). Note: This rejection assumes that the patient population has a virus.
The combination of Feige et al. in view of Zheng et al. have been described above and incorporated herein. In short, the combination of Feige et al. in view of Zheng et al. teach a method of administering trigonelline to a patient having Covid-19.
The combination does not specifically teach that the trigonelline is administered in combination with Wortmannin.
Selvaraj et a. teach the identification of potential drug targets and candidate drugs for COVID-19 (Title). Specifically, Selvaraj et al. teaches that repurposed Wortmannin as a candidate drug that can inhibit PI3K signaling and receptor tyrosine kinase (ERBB4) mediated micropinocytosis, to control virus cell proliferation and enhance ERBB4 functions namely alveolarization, morphogenesis and AEC2 differentiation (page 17 or 28, 1st column, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the method taught by the combination of Feige et al. and Zheng et al. to include administration of Wortmannin in view of the teachings of Selvaraj et al. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Selvaraj et al. teaches that repurposed Wortmannin as a candidate drug that can inhibit PI3K signaling and receptor tyrosine kinase (ERBB4) mediated micropinocytosis, to control virus cell proliferation and enhance ERBB4 functions namely alveolarization, morphogenesis and AEC2 differentiation.
In response to this rejection, Applicants contend that the combination of Feige and Zheng fails to render obvious the amended parent claims for the reasons discussed above. Regarding Selvaraj, Applicants assert that Selvaraj does not cure the deficiencies of Feige and Zheng because it is directed to identifying potential drug targets and candidate drugs for COVID-19 using biological networks and structural modeling approaches and does not disclose administering trigonelline with Wortmannin, does not disclose trigonelline attenuation of SAS-CoV-2 spike-protein-exacerbated lipotoxicity, and does not disclose the particular combination therapy now claimed. In particular, Applicants contend that the proposed combination relies on impermissible hindsight reconstruction with Applicants disclosure as a roadmap. However, the cited references do not themselves point to that combination or to the claimed therapeutic mechanism.
These arguments have been carefully considered but are not found persuasive.
The majority of Applicants arguments relating to the combination of Feige and Zheng and the claimed therapeutic mechanism have been responded to above and incorporated herein. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As noted in the rejection above, the combination of Feige et al. in view of Zheng et al. teach a method of administering trigonelline to a patient having Covid-19. The combination does not specifically teach that the trigonelline is administered in combination with Wortmannin. However, Selvaraj et al. teaches that repurposed Wortmannin as a candidate drug that can inhibit PI3K signaling and receptor tyrosine kinase (ERBB4) mediated micropinocytosis, to control virus cell proliferation and enhance ERBB4 functions namely alveolarization, morphogenesis and AEC2 differentiation. Thus, the motivation to combine the two agents is that each has been suggested/taught in the prior art for treatment of COVID-19. "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (See MPEP 2144.06 (I)).
New Rejection Necessitated by Amendment:
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 9 and 19 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.
Both claims 9 and 19 have been amended to recite that the methods of the independent claims “further comprise administering Wortmannin”. Thus, the claims have been amended to recite a combination treatment wherein Wortmannin is administered in combination with trigonelline. In the instant case, Applicants have not pointed to a specific portion of the specification which provides support for the limitation or provide any reasoning why support could be implicitly found. As noted in the prior office action (see rejection under 112 (d)), a review of the specification does not appear to contemplate a combination treatment. In particular, the specification appears to test each of the agents individually (see paragraph 0087). While the specification does mention combination kits (paragraph 0052), there is not a direct teaching or implicit teaching that such combination kits comprise both wortmannin and trigonelline. Accordingly, the claimed limitation appears to be new matter.
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 BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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BRANDON J. FETTEROLF, PHD
Primary Patent Examiner
Art Unit 1626
/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626
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