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 .
Claim Objections
(Previous objection, withdrawn) Claims 12 -16 recited “A method as claimed in”. The claims were amended to “The method of”.
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.
(Previous rejection, withdrawn) Claims 12 and 13 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description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.
Applicant has amended the claims.
Claim Rejections - 35 USC § 112- Scope of Enablement
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.
(Previous rejection, withdrawn) Claims 2, and 12-16, were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling vaccinating against SARS-CoV-2 viral infections by administering a SERM and a COVID-19 vaccine, does not reasonably provide enablement for preventing a . 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 these claims.
Applicant has amended the claims.
(New rejection, as necessitated by amendments) Claims 2, 12 – 16, and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for vaccinating a subject against COVID-19 while administering a Selective Estrogen Receptor Modulator (SERM), does not reasonably provide enablement for decreasing side effects resulting from the COVID-19 vaccine. 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 these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
• (A) The breadth of the claims;
• (B) The nature of the invention;
• (C) The state of the prior art;
• (D) The level of one of ordinary skill;
• (E) The level of predictability in the art;
• (F) The amount of direction provided by the inventor;
• (G) The existence of working examples; and
• (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Here, the instant claims are broadly drawn to a method of vaccinating a subject against COVID-19 the method comprising administering to the subject a combination of a SERM and a COVID-19 vaccine, wherein the SERM decreases side effects resulting from the COVID-19 vaccine.
The claims are not enabled based on, but not limited to, two major lines of evidence. First, the mechanism of action of SERMs as recited in the claims, would not likely decrease side effects caused by COVID-19 vaccines as recited in the claims. And second, not all side effects from COVID 19 vaccines are likely to be decreased by SERMs. The level of skill in the art is high and would include, e.g., Ph.D. level scientists.
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The art establishes that COVID 19 mRNA vaccines first enter cells before SARS-CoV-2 spike proteins are generated and trafficked to the surface of cells (Aim Health, 2020, reproduced below).
While the majority of spike proteins remain anchored to cells, Ogata et al (Clinical Infectious Diseases, 2022, 10.1093/cid/ciab465, hereinafter, “Ogata”) teaches there are a small amount of spike proteins found in circulation (Figure 1, Results ¶3). Ogata teaches portions of the S protein were found at concentrations of 62 pg/ml or 0.62 pM (Figure 1, Results ¶3). Although the reference postdates the effective filing date, it is probative of what a person of ordinary skill in the art would have known and understood about state of the art as of the effective filing date.
The specification only exemplifies and reduces cell proliferation of cells in the presence of raloxifene (Figure 6). Furthermore, cell proliferation of MDA-MB-231 cells, as shown in Figure 7, are not decreased in the presence of raloxifene, much less in the presence of the spike protein and raloxifene. Additionally, the concentration of spike protein applied to cells in the instant application is 10 ng/ml, which is 153.85 times physiological levels (10,000 pg/ml/ 65 pg/ml = 153.85). Ignoring the mechanism of COVID 19 mRNA vaccinations in which the majority of produced spike proteins are not circulating, the cell culture examples in the specification do not reflect average physiological conditions.
Furthermore, the COVID-19 mRNA vaccine is associated with many disparate side effects. Rogers et al (JHU HUB, 2020, “Side effects and COVID-19 vaccines: What to expect”, hereinafter, “Rogers”) teaches common side effects from COVID-19 mRNA vaccines include fatigue, headache, muscle aches, joint pain, and possibly fever (Section: What side effects should I expect from COVID-19 vaccines?). Raloxifene is not known to treat these side effects and can even induce them without a COVID-19 vaccine. Mayo Clinic (Retrieved 2020) teaches known side effects of raloxifene include joint pain, muscle pain, headaches, and fever. Sadovsky (American Family Physician, 1999) teaches raloxifene may cause fatigue.
The specification does not recite any working examples of decreasing side effects from a COVID-19 vaccine within a subject. Likewise, the Specification fails to disclose which dosages, administration routes, and administration routines are required to reduce the likelihood of COVID-19 side effects. At best, the Specification contemplates the use of the combination of a SERM and a COVID-19 vaccine in a subject. However, this is not sufficient to enable the claimed method because such methods can vary widely in efficacy.
Therefore, there is a reasonable expectation that a SARS-CoV-2 vaccine administered with a SERM as recited in the claims would not decrease the side effects of a COVID-19 vaccine an infection from SARS-CoV-2 in the absolute sense.
In view of the evidence discussed above, a vast quantity of experimentation, including expansive clinical trials, would be needed to use the invention based on the content of the disclosure.
Taken together, 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 these claims.
Claim Rejections - 35 USC § 103
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.
(Previous rejection, maintained and modified as necessitated by amendments) Claims 2 and 12 – 14 are rejected under 35 U.S.C. 103 as being unpatentable over Polack et al (NEJM, 2020, hereinafter, “Polack”), and in view of Chiou et al (J Enzyme Inhib Med Chem, 2021, hereinafter, “Chiou”), as evidenced by ASBMR (Joint Guidance on COVID-19 Vaccination and Osteoporosis Management from the ASBMR, AACE, Endocrine Society, ECTS, IOF, and NOF, retrieved, March 9th, 2021) and Vogel et al (Nature, 2021, 10.1038/s41586-021-03275-y, hereinafter, “Vogel”).
For purposes of compact prosecution and this rejection, prior art was applied to the enabled embodiments of claims 2 and 12 – 14 discussed above, i.e., a method for vaccinating against SARS-CoV-2 viral infections within a subject by administering a SERM and a COVID-19 vaccine.
Polack teaches the use of an mRNA Covid-19 vaccine to reduce the risk of SARS-CoV-2 infection in humans (Abstract). Polack teaches a large-scale trial of the vaccine with a 95% efficacy in reducing the risk of SARS-CoV-2 infection (Abstract). Furthermore, Polack teaches that this protective effect was observed in all demographic groups (Abstract). While Polack teaches the vaccine is effective, it is not able to prevent 100% of all cases (Abstract).
Chiou teaches that 3-chymotrypsin-like protease (3CL pro) found in coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2 are crucial to viral replication (Abstract) Chiou teaches that in the case of SARS-CoV-2, 3CLpro inhibitors such as the SERM raloxifene is a potent inhibitor (Abstract, Figure 2). Furthermore, Chiou teaches that raloxifene, also is known to inhibit other viral infections such as Ebola (Discussion ¶2).
Regarding claim 2, Polack teaches the administration of an mRNA vaccine against SARS-CoV-2 (Abstract). Chiou teaches that raloxifene is effective at inhibiting SARS-CoV-2 replication (Figure 2). ASBMR evidences the general guidelines of COVID-19 vaccination in patients with osteoporosis (¶1). ASBMR evidences the use of drugs in patients who have received the COVID-19 vaccine (Document as a whole). Regarding claim 2, ASBMR evidences “raloxifene should be continued in patients receiving COVID-19 vaccination” and that there “is no known interaction between raloxifene and COVID-19 vaccines, and raloxifene therapy does not cause an acute phase reaction.”
Regarding claims 12 and 13, Polack teaches the mRNA vaccine is directed against the SARS-CoV-2 spike protein (Methods). Furthermore, Vogel evidences the sequence of the BNT162b2 (abstract). Vogel evidences the vaccination profile of BNT162b2 in rhesus macaques (Abstract). Vogel evidences the BNT162b2 vaccine is comprised of a nucleotide sequence encoding the SARS-CoV-2 S protein with two proline substituted at residues 986 and 987 (Section: SARS-CoV-2 RBD–foldon and S(P2) expression and purification ¶3).
Regarding claim 14, Chiou teaches that raloxifene is a selective estrogen receptor modulator (Discussion ¶3).
Polack and Chiou are considered to be analogous to the claim invention because they both aim to treat human subjects. Polack teaches the use of an mRNA Covid-19 vaccine to reduce the risk of SARS-CoV-2 infection in humans (Abstract). Chiou teaches that raloxifene is effective at inhibiting SARS-CoV-2 replication (Figure 2).
Together, the prior art teaches that raloxifene can be used as an adjuvant to the mRNA vaccine against SARS-CoV-2. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have administered a mRNA Covid-19 vaccine and raloxifene in a subject because doing so would improve efficacy of SARS-CoV-2 vaccination. One of ordinary skill in the art would have had a reasonable expectation of success in administering both the mRNA Covid-19 vaccine and raloxifene in a subject given that the individual methods are well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claim(s) 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Pollack and Chiou as evidenced by ASBMR and Vogel as applied to claims 2 and 12 – 14 above, and further in view of Taurin et al (Int J Oncology, 2013, hereinafter, “Taurin”) as evidenced by Lal et al (Breast Cancer Res, 2013, hereinafter, “Lal”).
As discussed above, claims 2 and 12 – 14 were rendered prima facie obvious by Polack and Chiou. While the references teach the administration of raloxifene and a mRNA vaccine, the references fail to teach that raloxifene is a treatment for breast cancer or a physiological condition that alters hemostatic balance.
However, regarding claims 15 and 16, Taurin teaches raloxifene is a treatment for breast cancer (Abstract). Taurin teaches the therapeutic value of raloxifene in triple-negative breast cancer in mouse models (Abstract). Taurin teaches that mice received a daily oral treatment with different doses of raloxifene (Abstract.) Taurin teaches that a dosage of 0.85mg/kg prevents tumor growth and induces tumor regression (Abstract). Lal evidences the hemostatic changes during the progression of breast cancer (Abstract). Lal evidences that breast cancer alters hemostatic balance and that the hemostatic system is a potential target for novel therapeutic approaches (Abstract).
Polack, Chiou, and Taurin are considered to be analogous to the claim invention because they both aim to treat human subjects. Polack teaches the use of an mRNA Covid-19 vaccine to reduce the risk of SARS-CoV-2 infection in humans (Abstract). Chiou teaches that raloxifene is effective at inhibiting SARS-CoV-2 replication (Figure 2). Taurin teaches raloxifene is a treatment for breast cancer (Abstract).
Together, the prior art teaches that raloxifene can be used as an adjuvant to the mRNA vaccine against SARS-CoV-2. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have administered a mRNA Covid-19 vaccine and raloxifene in a subject diagnosed with breast cancer because doing so would dually target both breast cancer and improve efficacy of SARS-CoV-2 vaccination. One of ordinary skill in the art would have had a reasonable expectation of success in administering both the mRNA Covid-19 vaccine and raloxifene in a subject diagnosed with breast cancer given that the individual methods are well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claim(s) 26 is rejected under 35 U.S.C. 103 as being unpatentable over Pollack and Chiou as evidenced by ASBMR and Vogel as applied to claim 2 and 12 – 14 above, and further in view of Medline et al (Raloxifene, 2018, hereinafter, “Medline”)
As discussed above, claims 2 and 12 – 14 were rendered prima facie obvious by Polack and Chiou. While the references teach the administration of raloxifene and a mRNA vaccine, the references fail to teach that dosage regiment of a combination raloxifene and a mRNA vaccine.
However, Medline teaches the general usage and efficacy of raloxifene (Section: Why is this medication prescribed?). Medline also teaches the side effects and benefits of raloxifene (What special precautions should I follow?).
Regarding claim 26, Medline teaches raloxifene is administered orally once a day (Section: How should this medicine be used?). Polack teaches the mRNA vaccine is administered, by injection, twice in 21-day intervals (Methods). Therefore, the combination would be given separately according to standard guidelines of dosage regiments.
Polack, Chiou, and Medline are considered to be analogous to the claim invention because they both aim to treat human subjects. Polack teaches the use of an mRNA Covid-19 vaccine to reduce the risk of SARS-CoV-2 infection in humans (Abstract). Chiou teaches that raloxifene is effective at inhibiting SARS-CoV-2 replication (Figure 2). Medline teaches raloxifene is administered once a day (Section: How should this medicine be used?)
Together, the prior art teaches that raloxifene, administered orally once a day, can be used as an adjuvant to the mRNA vaccine, administered by injection, against SARS-CoV-2. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to have administered a mRNA Covid-19 vaccine and raloxifene separately in a subject because doing so would follow standard administration guidelines. One of ordinary skill in the art would have had a reasonable expectation of success in administering both the mRNA Covid-19 vaccine and raloxifene in a subject separately given that the individual methods are well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Response to Arguments
1) Applicant states the amendments to claims 12 -16 overcome the previous objections.
Applicant has amended the claims. Examiner has withdrawn the objection.
2) Applicant states amendments made to claims 12 overcomes the U.S.C. § 112 – Written Description
Applicant has amended claim 12. Examiner has withdrawn the rejection.
3) Applicant states amendments made to claim 2 overcomes the U.S.C. § 112 – Scope of
Enablement
Applicant has amended claim 2. Examiner has withdrawn the rejection.
4) Applicant states amendments made to claims 2 and 12 overcomes the U.S.C. § 103
a) Applicant states Chiou teaches the sole reduction of viral replication and not for vaccination purposes.
Applicant’s arguments have been fully considered but are not persuasive. Chiou teaches raloxifene inhibits viral replication through inhibition of the viral 3CL protease. Inhibitors do not need to be reactive to an infection, the presence of 3CLpro inhibitors can have a protective, i.e. vaccinating, effect on viral infection because they would inhibit viral replication which would reduce the likelihood of COVID-19 within a subject. The COVID-19 mRNA vaccine taught by Polack would ensure a robust priming of the immune system to quickly neutralize invading viruses. The combinatorial treatment of mRNA vaccine and a secondary line of defense with raloxifene would ensure that even if the mRNA vaccine failed to induce an immune response, viral replication would be inhibited in cells.
Furthermore, as discussed previously and above, ASBMR teaches that patients receiving raloxifene could be given a COVID-19 mRNA vaccine. Thus, at a minimum, the idea of a combinatorial use of raloxifene and COVID-19 mRNA vaccine in patients were contemplated at the time of filing.
b) Applicant has amended claims to include the limitation of wherein the SERM decreases side effects resulting from the COVID-19 vaccine. Applicant states the present invention is surprising, as the present inventors have discovered that a SERM can be used to reduce side effects of a COVID-19 vaccine.
Applicant’s arguments have been fully considered but are not persuasive. As discussed above, while the specification is enabled for the use of a combinatorial vaccine comprising a COVID-19 mRNA vaccine and raloxifene, the specification is not enabled for the reduction of COVID-19 vaccine mRNA side effects with the use of raloxifene. The specification only exemplifies a reduction of in some breast cancer cell proliferation in cell culture in the presence of spike proteins and raloxifene. However, as discussed above, not only does this not reflect physiological responses to a COVID-19 mRNA vaccine but raloxifene may exacerbate side effects such as joint pain, muscle aches, and fever. Furthermore, there is no information given as to the dosage, administration schedule, and administration routes that would enable the claims. Additionally, the present invention cannot be seen as surprising because, as discussed above, the specification, while being enabling for vaccinating a subject against COVID-19 while administering a Selective Estrogen Receptor Modulator (SERM), does not reasonably provide enablement for decreasing side effects resulting from the COVID-19 vaccine. An invention must be enabled to determine the criticality of unexpected results.
Conclusion
NO CLAIMS ARE ALLOWED
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 Danyal H Alam whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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/DANYAL HASSAN ALAM/Examiner, Art Unit 1672
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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