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 .
Election/Restrictions
Applicant’s election without traverse of Group 2, corresponding to claims 2, 12 - 16, and 25 and 26, as amended, in the reply filed on 01/13/2026 is acknowledged.
Claims 1, 3, 6 - 11, and 17 - 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 2, 12 – 16, 25 and 26 are under examination.
Priority
This is a National Stage Entry under 35 U.S.C. 371 of International Patent Application
No. PCT/EP2022/058688, filed March 31, 2022 and Foreign Patent Application, EP21166461.0, filed March 31, 2021.
Claim Objections
Claims 12 – 16 are objected to because of the following informalities:
Claims 12 -16 recite “A method as claimed in”. The claims should be amended to “The method of”. Appropriate correction is required.
Claim Interpretation
Regarding claims 2 and 12 – 16, for examination purposes claim 2 is interpreted as a method for preventing SARS-CoV-2 viral infections within a subject by administering a SERM and a COVID-19 vaccine, i.e., “COVID-19” was understood herein to mean the SARS-CoV-2 virus.
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 12 and 13 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.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.”
The claims are broadly drawn to a method of preventing COVID-19 in a subject by administering a combination of a selective estrogen receptor modulator (SERM) and a COVID-19 vaccine that uses the spike protein of SARS-CoV-2, a variant thereof or an immunogenic fragment thereof as an antigen. However, the Specification has failed to sufficiently describe the structural features that must be retained by the method and composition as to establish a structure-function relationship with respect to preventing COVID-19 within a subject using the spike protein of SARS-CoV-2, a variant of the SARS-CoV-2 spike protein, or an immunogenic fragment of SARS-CoV-2 spike protein.
The broadest reasonable interpretation of the claims encompasses innumerable variants and fragments of the SARS-CoV-2 spike protein. The Specification fails to disclose which variants can be used, which regions of the spike protein can be truncated, deleted, and/or which regions of must be retained to function as “immunogenic”.
Likewise, the Specification fails to disclose which regions, key amino acids, etc. must be must be retained to constitute a fragment or variant of the claimed SARS-CoV-2 spike protein. For example, tyrosine would seem to be a fragment of the SARS-CoV-2 spike protein, yet it is unclear if this constitutes an immunogenic SARS-CoV-2 spike protein fragment or variant since the Specification fails to describe any substantive structural limitations as to establish a structure-function relationship with respect to immunogenic function. The claims improperly define the genus based on what it does—not what it is.
While the claims are drawn to a nebulous genus of ill-defined variants and fragments (¶0053 – 0056) the Specification has only adequately described and successfully reduced to practice the SARS-CoV-2 spike protein binding with the estrogen receptor (Figure 8).
Moreover, Friedberg (Brief Bioinformatics, 7:225-242 (2006)) teaches that homology-based transfer is not reliable for functional annotation even with high alignment percentages (page 227, second column). Friedberg also teaches that identification of functionally significant sub-regions is critical to functional annotation, and that often addition, deletion, or re-shuffling
of domains can lead to errors in annotation (page 227, second column; page 228, first paragraph). Furthermore, Friedberg teaches that sequence-based tools are just not sensitive enough to identify functional protein similarity as databases get larger, and diversity of sequences gets larger (page 228, first full paragraph).
Thorton et al. (Nature Struct. Biol, Struct. Genom. Suppl. Nov., 991-994 (2000), hereinafter “Thorton”) teaches that the same protein structure is often seen in apparently different homologous families with different functions. Thorton further describes examples of little correlation between specific enzyme function and overall protein structure (page 992, right column, at lines 2-10). Thus, when taken with the teachings of Friedberg and Thorton, one of skill in the art would readily appreciate that sequence homology alone cannot serve as the basis to describe members of the genus that have the recited function.
In the absence of a representative number of examples, the Specification must at least
describe the structural features that are required for the claimed function, in this case “immunogenic” function. However, as discussed above, the Specification fails to describe any
substantive structural limitations as to establish a structure-function relationship with respect to “immunogenic” function. Applicant merely offers a cursory statement that any “SARS-COV-2 spike protein … that … contains one or more substitutions, deletions of internal ammino acids or insertions of one or more amino acids” will work. Applicant has improperly defined be genus by what it does rather than what it is.
Accordingly, the claims as currently written are not adequately described and one of skill in the art would readily appreciate that Applicant was not in possession of the claimed genus before the effective filing date of the claimed invention.
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.
Claims 2, and 12-16, 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 vaccinating against SARS-CoV-2 viral infections by administering a SERM and a COVID-19 vaccine, does not reasonably provide enablement for preventing a SARS-CoV-2 infection in the absolute sense. 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 for the prevention of SARS-CoV-2 infection within a subject by administering a SERM and a COVID-19 vaccine (See claim interpretation). In regard for prevention of a SARS-CoV-2 infection, it is noted that the term “preventing” was interpreted in an absolute sense to mean to always keep something from happening or arising.
The claims are not enabled based on, but not limited to, two major lines of evidence. First, not all SARS-CoV-2 infection are prevented by the recited COVID-19 vaccine. And second, not all SARS-CoV-2 infections are likely to be inhibited by SERMS and therefore a COVID-19 as recited in the claims along with a SERM adjuvant would not prevent an infection from SARS-CoV-2. The level of skill in the art is high and would include, e.g., Ph.D. level scientists.
The art establishes COVID 19 vaccine such as mRNA-based ones are not 100% effecting in preventing SARS-CoV-2 infection as evidenced by Polack et al (NEJM, 2020, hereinafter, “Polack”) (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).
Furthermore, Chiou (J Enzyme Inhib Med Chem, 2021, hereinafter, “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). Chiou also teaches that raloxifene is not 100% effective at inhibiting its target (Figure 2).
Moreover, Meo (Eur Rev Med Pharmacol Sci, 2021, hereinafter, “Meo”) teaches that COVID-19 vaccines are not identical in efficacy. Meo teaches that the Pfizer/BioNTech vaccine results in 95% vaccine efficacy while the Moderna vaccine results in 94.5% (Results). Walls (Cell, 2020, hereinafter, “Walls”) teaches the antibody response by RBD nanoparticle vaccines for SARS-CoV-2 (Abstract). Walls teaches even slight changes, such as additional linker sequences, resulted in different immunogenicity (Figure 4). This difference in immunity highlights that not all vaccines are equivalent. Additionally, Walls teaches that the RBD protein itself did not lead to antibody response (Figure 4). Thus, when taken with the teachings of Meo and Wall, one of skill in the art would readily appreciate that a vague notion of a COVID-19 vaccine alone cannot serve as the basis to describe the method to have the recited function of preventing COVID-19.
Therefore, there is a reasonable expectation that a SARS-CoV-2 vaccine administered with a SERM adjuvant as recited in the claims would not prevent an infection from SARS-CoV-2 in the absolute sense.
In view of the evidence discussed above, the combination COVID-19 vaccine administered with a SERM adjuvant would not predictably prevent all SAR-CoV-2 viral infections.
The specification only exemplifies and reduces binding of the SARS-CoV-2 spike protein to an estrogen receptor in the presence of estradiol and raloxifene in cell culture (see Figure 8). The specification does not recite any working examples of preventing a SARS-CoV-2 infection within a subject. Likewise, the Specification fails to disclose which dosages, administration routes, and administration routines must be must be retained to reduce the likelihood of SARS-CoV-2 infection. 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 describe the claimed method because such methods can vary widely in efficacy.
In view of the foregoing, 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.
Claims 2, 12 – 14, and 25 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).
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 and 25, 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).
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 as applied to claims 2, 12 – 14, and 25 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, 12 – 14, and 25 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 that breast cancer 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 as applied to claim 2, 12 – 14, and 25 above, and further in view of Medline et al (Raloxifene, 2018, hereinafter, “Medline”)
As discussed above, claims 2, 12 – 14, and 25 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.
Conclusion
NO CLAIMS ARE ALLOWED
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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