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 .
Priority
Priority to US 63/139,652, filed 1/20/2021, is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) was/were submitted on 6/6/2024 and 3/25/205, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 54-72, filed 7/19/2023, are pending. Claims 54-72 are under examination.
Claim Objections
Claims 54-72 are objected to because of the following informalities. Claims 54-72 lack claim identifiers such as “currently amended”. MPEP 37 C.F.R. 1.121(c) states: “In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered). Appropriate correction is required.
Claims 63, 65, 70, and 72 are objected to because of the following informalities. Claims 63, 65, 70, and 72 would be more consistent if they stated “The method of claim 54, further comprising”. Appropriate correction is required.
Claim Interpretation
For purposes of compact prosecution, claim 71 will be interpreted as depending from claim 70. Claim 70 refers to “… the formulation with an antibody directed to the coronavirus.” Claim 71 refers to “where in the antibody is selected from the group consisting of…”. No other claims refer to an “antibody”.
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 56, 57, 59, 67, and 68 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 claim 56, claim 56 recites the limitation "first protease activity" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 56 is rejected.
Regarding claim 57, claim 57 recites the limitation "first protease activity" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 57 is rejected.
Regarding claim 59, claim 59 recites the limitation “single molecular species”. It is not clear what limitations are created by the phrase “single molecular species”. Based off the specification, it would be more clear to use the phrase “embodied in a cyclic peptide”. Claim 59 is rejected.
Regarding claim 67, claim 67 recites “… a naturally occurring cyclic peptide or a synthetic cyclic peptide…” It is not clear which of these peptides confers the first protease inhibitor activity and anti-inflammatory activity from claim 54. Clarification is required. Claim 67 is rejected.
Regarding claim 68, claim 68 recites “… a naturally occurring cyclic peptide or a synthetic cyclic peptide…” It is not clear which of these peptides confers the first protease inhibitor activity and anti-inflammatory activity from claim 54. Clarification is required. Claim 68 is rejected.
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 54-57, 59-60, 63, and 65-72 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 protease inhibitor activities against zinc metalloproteinases (ADAMs and MMPs) and cysteine cathepsins possessed by SEQ ID NO: 1, or RTD-1 and for anti-inflammatory activity tied to reducing cytokine response, does not reasonably provide enablement for any possible protease inhibitor activity or for any possible anti-inflammatory activity. 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.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024). These factors include, but are not limited to:
(A) The breadth of the claims;
Claim 54 is broad with respect to the number of types of protease inhibitor activity claimed and the anti-inflammatory activity claimed.
(B) The nature of the invention;
The invention is a method of treating an individual for infection by a coronavirus.
(C) The state of the prior art;
Schaal et al. (Schaal, et al. PLoS One 12.11: e0187868 (2017)) discloses protease activity of RTD-1: “RTD-1 was analyzed for enzymatic inhibition against zinc metalloproteases ADAM17, ADAM10, matrix metalloproteases (MMPs) 1, 2, 3, 8, 9, 13, and 14, and cysteine cathepsins (Cats) B, C, H, K, L, S, and V (Table 1).” (Schaal et al., page 5, para. 5 and Table 1). These protease activities are tied to the modulation of TNFα and ultimately cytokines such as IL-6: “The inhibitory action of RTD-1 on arthritogenic proteases, including MMPs and cathepsin K, suggests another anti-arthritic mechanism that may be operative in vivo. Results of the current study demonstrate that RTD-1 is a cross class anti-protease that inhibits zinc metalloproteinases (ADAMs and MMPs) and cysteine cathepsins. The inhibitory potency of RTD-1 against a panel of MMPs and cathepsins varies substantially, but plasma levels (Cmax) achieved following s.c. treatment approximate or exceed the IC50s of ADAM17 and cathepsin K, potentially providing a rapid mechanism for regulating these arthritogenic proteases, in the former case down-regulating local TNFα levels and downstream effects (e.g., IL-1β, IL-6, MMP expression). This may also contribute to inhibition of FLS invasiveness mediated by low concentrations of RTD-1.” (Schaal et al, page 13, para. 4).
(D) The level of one of ordinary skill;
A person of ordinary skill in the art in the field of fusion proteins is usually at least a Master’s level education.
(E) The level of predictability in the art;
The inflammatory system and immune system are very complex. Schaal et al. provides a good explanation for how the disclosed protease activities influence inflammation through TNFα and IL-6 cascades, but the specification does not disclose how other protease activities not possessed by RTD-1 and related peptides are relevant to treating coronaviruses.
(F) The existence of working examples and amount of direction provided by the inventor;
Applicant discloses several protease targets of RTD-1, such as TMPRSS2, Cathepsin B/L, and furin. However, the claim scope of claim 54 is any possible protease inhibitor activity.
(G) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
It would require a great deal of experimentation to test all protease activities for their efficacy in treating coronaviruses.
Regarding claim 54, the scope of claim 54 encompasses any possible protease activity. Furthermore, RTD-1 functions through reduction of proinflammatory cytokines: “… in the presence of SARS-CoV, RTD-1-treated animals show blunted proinflammatory cytokine responses in lung tissue 2 and 4 days postinfection and have a marked reduction in mortality. One possible mechanism is that RTD-1 serves as an inducer (or accelerator) of antiviral responses. Another possibility is that RTD-1 reduces viral bronchiolitis and/or diffuse alveolar damage. Finally, perhaps RTD-1 reduces pulmonary inflammation, thereby diminishing systemic
dissemination of the pathogen.” (Wohlford-Lenane et al., page 11388, col. 2, para. 1).
Because of this specific anti-inflammatory mechanism, RTD-1 does not necessarily modulate inflammation caused by systems that do not involve cytokines.
For the reasons described above, 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.
Consequently, claim 54 is rejected.
Regarding claim 55, claim 55 does not reduce the scope of the claimed protease inhibitor activities or the anti-inflammatory activity. Consequently, claim 55 is rejected.
Regarding claim 56, claim 56 reduces the scope of the claim to any serine protease inhibitor, any cysteine protease inhibitor, or any metalloprotease inhibitor. These are still extremely broad groups of inhibitors, and 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.
Consequently, claim 56 is rejected.
Regarding claim 57, claim 57 reduces the scope of the claim to any serine protease inhibitor, any cysteine protease inhibitor, and any metalloprotease inhibitor. These are still extremely broad groups of inhibitors, and 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.
Consequently, claim 57 is rejected.
Regarding claim 59, claim 59 does not reduce the scope of the claimed protease inhibitor activities or the anti-inflammatory activity. Consequently, claim 59 is rejected.
Regarding claim 60, claim 60 does not reduce the scope of the claimed protease inhibitor activities or the anti-inflammatory activity. Consequently, claim 60 is rejected.
Regarding claim 63, claim 63 does not reduce the scope of the claimed protease inhibitor activities or the anti-inflammatory activity. Consequently, claim 63 is rejected.
Regarding claims 65-72, these claims do not reduce the scope of the claimed protease inhibitor activities or the anti-inflammatory activity. Consequently, claims 65-72 are rejected.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 54 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wohlford-Lenane et al. (Wohlford-Lenane, et al. Journal of virology 83.21: 11385-11390. (2009)) as evidenced by Schaal, et al. (Schaal, et al. PLoS One 12.11: e0187868 (2017)).
Regarding claim 54, claim 54 recites a method of treating an individual for infection by a coronavirus, comprising: determining that the individual is in need of treatment of infection by the coronavirus; and administering a formulation comprising a first protease inhibitor activity and an anti- inflammatory activity.
Wohlford-Leane et al. discloses the usage of RTD-1 for treatment of a coronavirus: “We evaluated the efficacy of rhesus theta-defensin 1 (RTD-1), a novel cyclic antimicrobial peptide, as a prophylactic antiviral in a mouse model of severe acute respiratory syndrome (SARS) coronavirus (CoV) lung disease. BALB/c mice exposed to a mouse-adapted strain of SARS-CoV demonstrated 100% survival and modest reductions in lung pathology without reductions in virus titer when treated with two intranasal doses of RTD-1, while mortality in untreated mice was ∼75%. RTD-1-treated, SARS-CoV-infected mice displayed altered lung tissue cytokine responses 2 and 4 days postinfection compared to those of untreated animals, suggesting that one possible mechanism of action for RTD-1 is immunomodulatory.” (Wohlford-Leane et al., page 11385, Abstract).
Regarding the protease activity, Schaal et al. discloses that RTD-1 possesses protease inhibitor activity: “Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFα, and inhibited matrix metalloproteases, and cathepsin K.” (Schaal et al., page 1, Abstract).
Regarding the anti-inflammatory activity, Wohlford-Leane et al. discloses that RTD-1 reduces inflammation through regulation of proinflammatory cytokine responses: “There are several possible mechanisms by which RTD-1 modifies the lung disease course. While the peptide alone appears to directly induce some dose-dependent airway inflammation, in the presence of SARS-CoV, RTD-1-treated animals show blunted proinflammatory cytokine responses in lung tissue 2 and 4 days postinfection and have a marked reduction in mortality. One possible mechanism is that RTD-1 serves as an inducer (or accelerator) of antiviral responses. Another possibility is that RTD-1 reduces viral bronchiolitis and/or diffuse alveolar damage. Finally, perhaps RTD-1 reduces pulmonary inflammation, thereby diminishing systemic dissemination of the pathogen. It remains to be determined whether there is a mechanistic relationship between the mild inflammation induced by RTD-1 in uninfected mice and the protective effect of the peptide observed in virus-challenged animals. This will require a more comprehensive analysis of cellular and soluble inflammatory responses. Moreover, since RTD-1 does not appear to have direct antiviral effects, its potential for modulating viral spread is likely to depend on the ability of the peptide to limit viral proliferation and shedding at the level of the individual animal. Further investigation of this novel agent is warranted.” (Wohlford-Leane et al., page 11388, col. 1, para. 3).
Regarding determining that the individual is in need of treatment, Wohlford-Leane discloses mice in need of treatment: “We inoculated groups of mice with 3 × 105 PFU of MA15 SARS-CoV (28), a dose previously shown to cause ∼75% mortality (J. Zhao, J. Zhao, N. Van Rooijen, and S. Perlman, submitted for publication). As shown in Fig. 1A, infected mice began to lose weight within 2 to 3 days of inoculation and continued to do so until they succumbed to the infection or recovered.” (Wohlford-Leane et al., page 11385, col. 2, para. 2).
Consequently, claim 54 is anticipated by Wohlford-Leane et al. as evidenced by Schaal et al. and rejected.
Regarding claim 56, claim 54 is anticipated as described above. Claim 56 further recites the case wherein the first protease activity comprises at least one of a serine protease inhibitor activity, a cysteine protease inhibitor activity, and a metalloprotease activity. Schaal et al. discloses that RTD-1 possesses metalloprotease inhibitor activity: “Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFα, and inhibited matrix metalloproteases, and cathepsin K.” (Schaal et al., page 1, Abstract).
Consequently, claim 56 is anticipated by Wohlford-Leane et al. as evidenced by Schaal et al. and rejected.
Regarding claim 57, claim 54 is anticipated as described above. Claim 56 further recites the case wherein the first protease activity comprises a serine protease inhibitor activity, a cysteine protease inhibitor activity, and a metalloprotease inhibitor activity. Schaal et al. discloses that RTD-1 possesses metalloprotease inhibitor activity: “Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFα, and inhibited matrix metalloproteases, and cathepsin K.” (Schaal et al., page 1, Abstract).
Regarding the serine protease activity and cysteine protease inhibitor activity, the method is already anticipated as described above. MPEP 2112(I) states: “"[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).”
These additional protease activities are unappreciated properties of an anticipated method.
Consequently, claim 57 is anticipated by Wohlford-Leane et al. as evidenced by Schaal et al. and rejected.
Regarding claim 58, claim 54 is anticipated as described above. Claim 58 further recites the case wherein the first protease inhibitor activity is selected from the group consisting of inhibition of TMPRSS2, inhibition of Cathepsin B/L (CatB/L), and inhibition of furin.
Regarding the inhibition of TMPRSS2, inhibition of Cathepsin B/L (CatB/L), and inhibition of furin, the method is already anticipated as described above. Schaal et al. discloses that RTD-1 inhibits Cathepsin B with an IC50 is 1 μM and Cathepsin L with a an IC50 of 1.4 μM (Schaal et al., page 6, Table 1).
Furthermore, MPEP 2112(I) states: “"[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).”
Consequently, claim 58 is anticipated by Wohlford-Leane et al. as evidenced by Schaal et al. and rejected.
Regarding claim 59, claim 54 is anticipated as described above. Claim 59 further recites the case wherein the first protease activity and the anti-inflammatory activity are embodied in a single molecular species.
Regarding the protease activity, Schaal et al. discloses that RTD-1 possesses protease inhibitor activity: “Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFα, and inhibited matrix metalloproteases, and cathepsin K.” (Schaal et al., page 1, Abstract).
Regarding the anti-inflammatory activity, Wohlford-Leane et al. discloses that RTD-1 reduces inflammation through regulation of proinflammatory cytokine responses: “There are several possible mechanisms by which RTD-1 modifies the lung disease course. While the peptide alone appears to directly induce some dose-dependent airway inflammation, in the presence of SARS-CoV, RTD-1-treated animals show blunted proinflammatory cytokine responses in lung tissue 2 and 4 days postinfection and have a marked reduction in mortality. One possible mechanism is that RTD-1 serves as an inducer (or accelerator) of antiviral responses. Another possibility is that RTD-1 reduces viral bronchiolitis and/or diffuse alveolar damage. Finally, perhaps RTD-1 reduces pulmonary inflammation, thereby diminishing systemic dissemination of the pathogen. It remains to be determined whether there is a mechanistic relationship between the mild inflammation induced by RTD-1 in uninfected mice and the protective effect of the peptide observed in virus-challenged animals. This will require a more comprehensive analysis of cellular and soluble inflammatory responses. Moreover, since RTD-1 does not appear to have direct antiviral effects, its potential for modulating viral spread is likely to depend on the ability of the peptide to limit viral proliferation and shedding at the level of the individual animal. Further investigation of this novel agent is warranted.” (Wohlford-Leane et al., page 11388, col. 1, para. 3).
RTD-1 possesses both activities; consequently, claim 59 is anticipated by Wohlford-Leane et al. as evidenced by Schaal et al. and rejected.
Regarding claim 60, claim 54 is anticipated as described above. Claim 60 further recites the case wherein the formulation further comprises a second protease inhibitor activity, and wherein the anti-inflammatory activity comprises the second protease inhibitor activity.
As described above, RTD-1 possesses combined anti-inflammatory and protease inhibitor activity. Schaal et al. discloses that RTD- possess multiple protease activities such as ADAM variants, Cathepsin variants, and MMP variants. (Schaal et al., page 6, Table 1). Therefore, the formulation utilizing RTD-1 has a second protease inhibitor activity and the anti-inflammatory activity comprises the second protease inhibitor activity.
Consequently, claim 60 is anticipated by Wohlford-Leane et al. as evidenced by Schaal et al. and rejected.
Regarding claim 61, claim 60 is anticipated as described above. Claim 61 further recites the case wherein the second protease inhibitor activity reduces processing of a pro-inflammatory cytokine.
Schaal et al. discloses that the protease activities discussed above are at least partially responsible for down regulation of TNFα and consequently IL-6 and other pro-inflammatory cytokines:
“The inhibitory action of RTD-1 on arthritogenic proteases, including MMPs and cathepsin K, suggests another anti-arthritic mechanism that may be operative in vivo. Results of the current study demonstrate that RTD-1 is a cross class anti-protease that inhibits zinc metalloproteinases (ADAMs and MMPs) and cysteine cathepsins. The inhibitory potency of RTD-1 against a panel of MMPs and cathepsins varies substantially, but plasma levels (Cmax) achieved following s.c. treatment approximate or exceed the IC50s of ADAM17 and cathepsin K, potentially providing a rapid mechanism for regulating these arthritogenic proteases, in the former case down-regulating local TNFα levels and downstream effects (e.g., IL-1β, IL-6, MMP expression). This may also contribute to inhibition of FLS invasiveness mediated by low concentrations of RTD-1.” (Schaal et al., page 13, para. 4).
Consequently, claim 61 is anticipated by Wohlford-Leane et al. as evidenced by Schaal et al. and rejected.
Regarding claim 62, claim 60 is anticipated as described above. Claim 62 further recites the case wherein the second protease inhibitor activity inhibits a sheddase.
Schaal et al. discloses that: “RTD-1 was found to be a potent inhibitor of ADAM17 as well as ADAM10, a related proTNF sheddase (Table 1)”. (Schaal et al., page 12, para. 2). This protease activity may be the second protease activity.
Consequently, claim 62 is anticipated by Wohlford-Leane et al. as evidenced by Schaal et al. and rejected.
Regarding claim 63, claim 54 is anticipated as described above. Claim 63 further recites the case wherein the formulation comprises a naturally occurring cyclic peptide exhibiting both the first protease inhibitor activity and the anti-inflammatory activity.
Wohlford-Leane discloses that RTD-1 is a natural cyclic peptide: “Rhesus theta-defensin 1 (RTD-1) is a unique cyclic antimicrobial peptide first identified in rhesus macaque leukocytes.” (Wohlford-Leane et al., page 11385, col. 1, para. 3). As discussed above. RTD-1 possesses both anti-inflammatory and protease inhibitor activity.
Consequently, claim 63 is anticipated by Wohlford-Leane et al. as evidenced by Schaal et al. and rejected.
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.
Claims 64-68 are rejected under 35 U.S.C. 103 as being unpatentable over Wohlford-Lenane et al. (Wohlford-Lenane, et al. Journal of virology 83.21: 11385-11390. (2009)) as evidenced by Schaal, et al. (Schaal, et al. PLoS One 12.11: e0187868 (2017)), as applied to claim 54 above, further in view of Schaal, et al. (Schaal, et al. PLoS One 12.11: e0187868 (2017)).
Regarding claim 64, claim 63 is obvious as described above. Claim 64 further recites the case wherein the naturally occurring cyclic peptide is selected from the group consisting of Peptide 1 (SEQ ID NO. 1), Peptide 2 (SEQ ID NO. 2), Peptide 3 (SEQ ID NO. 3), Peptide 4 (SEQ ID NO. 4), Peptide 5 (SEQ ID NO. 5), Peptide 6 (SEQ ID NO. 6), Peptide 7 (SEQ ID NO. 7), Peptide 8 (SEQ ID NO. 8), Peptide 9 (SEQ ID NO. 9), Peptide 10 (SEQ ID NO. 10), Peptide 11 (SEQ ID NO. 11), Peptide 12 (SEQ ID NO. 12), Peptide 13 (SEQ ID NO. 13), Peptide 14 (SEQ ID NO. 14), Peptide 15 (SEQ ID NO. 15), Peptide 16 (SEQ ID NO. 16).
Schaal et al. discloses the cyclic peptide: GFCRCLCRRGVCRCICTR (Schaal et al., page 3, Fig. 1). This cyclic peptide reads on Applicant SEQ ID NO: 1.
Consequently, claim 64 is obvious over Wohlford-Leane et al. in view of Schaal et al. and rejected.
Regarding claim 65, claim 54 is anticipated as described above. Claim 65 further recites the case wherein administration comprises systemic administration of the formulation.
Schaal et al. discloses the systemic administration of RTD-1: “RTD-1 dissolved in saline was injected subcutaneously at 5 mg/kg to 4 animals.“
Consequently, claim 65 is obvious over Wohlford-Leane et al. in view of Schaal et al. and rejected.
Regarding claim 66, claim 65 is obvious as described above. Claim 66 further recites the case wherein systemic administration comprises intravenous administration of the formulation.
Schaal et al. discloses that RTD-1 may be administered by intravenous routes: “The results of this study indicate that θ-defensin-like cyclic peptides have potential as new agents for treatment of RA. RTD-1 itself is a pharmaceutical candidate as this naturally occurring molecule is well tolerated when administered subcutaneously (this study and ref. [9]), and by intravenous, intramuscular, and intraperitoneal routes (our unpublished results)” (Schaal, et al, page 14, para. 3).
A person of ordinary skill in the art would use the disclose of Schaal and then utilize intravenous administration as a matter of routine optimization (MPEP 2144.05(II) and selection from a number of limited, finite choices of administration.
Consequently, claim 66 is obvious over Wohlford-Leane et al. in view of Schaal et al. and rejected.
Regarding claim 67, claim 66 is obvious as described above. Claim 67 further recites the case wherein intravenous administration comprises injection to provide a naturally occurring cyclic peptide or a synthetic cyclic peptide in an amount sufficient to provide more than 5 mg/kg.
MPEP 2144.05(II) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
The recited dosage for the claimed cyclic peptide is a matter of routine optimization and therefore will not support patentability.
Consequently, claim 67 is obvious over Wohlford-Leane et al. in view of Schaal et al. and rejected.
Regarding claim 68, claim 67 is obvious as described above. Claim 68 further recites the case wherein intravenous administration comprises injection to provide a naturally occurring cyclic peptide or a synthetic cyclic peptide in an amount sufficient to provide less than or equal to 20 mg/kg.
MPEP 2144.05(II) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
The recited dosage for the claimed cyclic peptide is a matter of routine optimization and therefore will not support patentability.
Consequently, claim 68 is obvious over Wohlford-Leane et al. in view of Schaal et al. and rejected.
Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over Wohlford-Lenane et al. (Wohlford-Lenane, et al. Journal of virology 83.21: 11385-11390. (2009)) as evidenced by Schaal, et al. (Schaal, et al. PLoS One 12.11: e0187868 (2017)) as applied to claim 54 above, and further in view of Ragab et al. (Ragab, et al. Frontiers in immunology 11: 551898. (2020)) and Mahendran et al. (Mahendran, et al. Frontiers in pharmacology 11: 575444 (2020)).
Regarding claim 55, claim 54 is anticipated as described above. Claim 55 further recites the case wherein the coronavirus is SARS-CoV-2.
The method of Wohlford-Leane and Schaal does not specifically disclose SARS-CoV-2. However, Wohlford-Leane discloses that RTD-1 modifies the activity of cytokines during SARS-CoV infections: “Among the hypotheses proposed to explain the morbidity and mortality associated with SARS is the notion that overly exuberant cytokine/chemokine responses or repressed innate immune responses contribute (11, 29, 40). We assessed cytokine responses in lung tissue homogenates at 2 and 4 days postinfection. At 2 days postinfection, interleukin-6 (IL-6), Keratinocyte chemoattractant, and granulocyte colony-stimulating factor were increased in SARS-CoV-infected mice treated with RTD-1 compared to mice infected with SARS-CoV alone. Mice treated with RTD-1 and infected with SARS-CoV displayed significant reductions in levels of RANTES at day 2 postinfection (Fig. 3A, top panels) and reductions in levels of IL-1α, IL-1β, IL-6, Keratinocyte chemoattractant, MIP1α, monocyte chemoattractant protein 1, and IL-12(p40) at day 4 postinfection (Fig. 3B, bottom panels) compared to those in SARS-CoV-infected mice that received no RTD-1. There were no significant changes in tissue gamma interferon (Fig. 3) or type I interferons (quantitative reverse transcription-PCR, data not shown). Thus, while RTD-1 had no significant direct inhibitory effect on MA15 virus titer in vivo or in vitro (Fig. 1C and D), it may alter disease outcome by modifying cytokine responses to infection.” (Wohford-Leane et al., page 11386, col. 2, para. 2).
Ragab et al. discloses that cytokine activity is also implicated in SARS-CoV-2 COVID-19 cases: “Accumulating evidence suggests that some patients with severe COVID-19 suffer from a “cytokine storm.” Analysis of cytokine levels in plasma of 41 COVID-19 confirmed cases in China revealed elevated levels of IL-1β, IL-7, IL-8, IL-9, IL-10, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1A, MIP1-B, PDGF, TNF-α, and VEGF in both patients admitted to the ICU and non-ICU patients compared to healthy adults. All patients included in the study had pneumonia and 1/3 of the patients were admitted to ICU and six of these patients died (16).
A multicenter retrospective study of 150 COVID-19 patients in China evaluated predictors of mortality for COVID-19. The study analyzed data from 82 cases who resolved from COVID-19 and 68 cases who died from COVID-19 and reported significantly higher levels of IL-6 in mortality cases than resolving cases (20). Another study analyzing data from 21 patients in China reported increased levels of IL-10, IL-6, and TNF-α in severe cases (n = 11 patients) compared to moderate cases (n = 10 patients) (21). A similar study by Gao et al. assessed 43 patients in China and reported that levels of IL-6 were significantly higher in severe cases (n = 15) than in mild cases (n = 28) (22). Similarly, Chen et al. studied a total of 29 COVID-19 patients, divided into three groups according to relevant diagnostic criteria, and found that IL-6 was higher in critical cases (n = 5 patients) than in severe cases (n = 9 patients) and that IL-6 was higher in severe cases than in mild cases (n = 15 cases) (23).” (Ragab et al., page 3, col. 1, para. 2).
Mahendran et al. discloses that this approach was known and contemplated in the community: “Antiviral Immunomodulatory Effect
The cyclic peptide RTD-1 (GFCRCLCRRGVCRCICTR) from rhesus macaque leukocytes was reported to decrease disease pathogenesis of SARS-CoV infection in mice, as observed with a substantial reduction in perivascular infiltrate and necrotizing bronchiolitis (Wohlford-Lenane et al., 2009). Interestingly, neither did RTD-1 inhibit the virus or interact with the host cell receptors to exert an antiviral effect. In contrast, it was noticed that the virus titers and lung tissue nucleocapsid (N) gene antigen expression were similar to the untreated control mice. Together with an increase in cytokine levels of interleukin-6, keratinocyte chemoattractant, and granulocyte colony-stimulating factor in lung cell homogenates, RTD-1 was suggested to act as an immunomodulatory effector molecule via a blunted proinflammatory cytokine response in eliminating SARS-CoV (Wohlford-Lenane et al., 2009).
Prioritization and emergency preparedness in responding to the emerging infectious diseases associated with outbreaks and pandemics are of utmost urgency. In search of an effective antiviral against COVID-19, we believe AVPs could represent one of the potential classes of new antiviral agents against SARS-CoV-2. It is fascinating to discover how AVPs, composed principally of short and simple amino acid sequences, could interact with and specifically target the different viral components to achieve potent antiviral effects. Here, we would like to bring the attention to a number of AVPs with highly promising anti-CoV activities: mucroporin-M1 disrupts viral envelope, HR2P-M2 targets the viral S protein-mediated fusion mechanism, EK1 and EK1C4 block the HR1 domain of viral S2 subunit, and P9 peptide inhibits late endosomal acidification and thus preventing viral RNA release. Besides, there are AVPs that confer protection to the host: RTD-1 is an antiviral immunomodulator that triggers protective immunity; HD5 binds to and shields host ACE2 receptor to prevent viral recognition and attachment.” (Mahendran et al., page 4, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method of Wohlford-Leane and Schaal to treat COVID-19 caused by SARS-CoV-2 to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use the method of Wohlford-Leane and Schaal to treat COVID-19 because COVID-19 is a highly dangerous infection: “COVID-19 is a rapidly spreading global threat that has been declared as a pandemic by the WHO. COVID-19 is transmitted via droplets or direct contact and infects the respiratory tract resulting in pneumonia in most of the cases and acute respiratory distress syndrome (ARDS) in about 15 % of the cases. Mortality in COVID-19 patients has been linked to the presence of the so-called “cytokine storm” induced by the virus.” (Ragab, page 1, Abstract). Also, COVID-19 is known to be caused by SARS-CoV-2 virus: “COVID-19 is caused by the SARS-CoV-2 that belongs to the beta-coronaviruses subfamily.” (Ragab, page 1, para. 2).
A person of ordinary skill in the art would have a reasonable expectation of expectation of success because as Wohlford-Leane discloses above, RTD-1 is able to modulate cytokines that Ragab discloses are associated with negative outcomes in cases of COVID-19. The disclosure of Mahendran above further demonstrates that persons of ordinary skill in the art would have a reasonable expectation of success of this treatment method.
Consequently, claim 55 is obvious over Wohlford-Leane et al. as evidenced by Schaal et al. as applied to claim 54 above, further in view of Ragba et al. and Mahendran et al. and rejected.
Claim 69 is rejected under 35 U.S.C. 103 as being unpatentable over Wohlford-Lenane et al. (Wohlford-Lenane, et al. Journal of virology 83.21: 11385-11390. (2009)) as evidenced by Schaal, et al. (Schaal, et al. PLoS One 12.11: e0187868 (2017)) as applied to claim 54 above, and further in view of Johnson (Johnson, Keith A. Advanced drug delivery reviews 26.1: 3-15. (1997)).
Regarding claim 69, claim 54 is anticipated as described above. Claim 69 further recites the case wherein the formulation is provided as a droplet suspension, and wherein administration comprises inhalation of the droplet suspension.
The method of Wohlford-Leane and Schaal does not specifically disclose such a delivery method. However, Johnson discusses inhalation of therapeutic peptides:
“Delivering therapeutic proteins and peptides by aerosol has many advantages. If the bloodstream is the target, macromolecules can pass from the alveolar epithelium to the blood by a natural process that does not require a penetration enhancer. Removing the requirement of a penetration enhancer simplifies the formulation and reduces potential toxicological issues. Therapeutic aerosols for respiratory diseases reach the site of action directly, which usually requires smaller doses and reduces the potential for unwanted side effects. Aerosol delivery can also lead to more rapid onset of action when compared to oral or parenteral routes. While aerosols have many advantages as a macromolecule drug delivery system, consistently depositing a high percentage of the dose in the alveolar region is a significant pharmaceutical and technological challenge. The remainder of this paper will review techniques for preparing macromolecule drug aerosols, with particular attention to the preparation of fine powders.” (Johnson, page 4, col. 2, para. 2).
Johnson also discusses how these formulations are in droplet form: “Proteins and peptides can be stabilized by synthetic and formulation techniques. Synthetic techniques such as crosslinking, adding anion and cation binding sites and amino acid substitution have improved the stability for some macromolecule drugs 33, 34. Stability can also be improved by adding excipients such as polyols, salts and surface active agents to the solution 35, 36. Cooling solutions of macromolecules to subzero temperatures is also effective for preserving their chemical and physical structure [37]. Under-cooled solutions remain unfrozen by adding compounds that depress the freezing point or by dispersing the formulation as fine droplets in a continuous organic phase. (Johnson, page 7, col. 1, para. 3).
A person of ordinary skill in the art would be motivated to use this delivery method to enhance patient compliance as disclosed by Johnson: “Poor compliance with the prescribed regimens can lead to increased medical complications. In addition, some elderly, infirm, or pediatric patients cannot administer their own injections and require assistance, thereby increasing inconvenience to these patients and the cost of their therapy. An ideal drug delivery system would be safe, reproducible, non-invasive, convenient and have high bioavailability.” (Johnson, page 4, col. 1, para. 1)
A person of ordinary skill in the art would have a reasonable expectation of success due to how such administration can reduce protein or peptide degradation: “Macromolecule drug delivery by dry powder inhalation has many advantages over other delivery techniques. Inhalation is non-invasive and macromolecules deposited in the alveolar region can be absorbed into the bloodstream without using a penetration enhancer. Formulating the protein as a solid avoids many degradation problems observed in solution formulations.” (Johnson, page 12, col. 2, para. 4).
Consequently, claim 69 is obvious over Wohlford-Leane et al. as evidenced by Schaal et al. as applied to claim 54 above, further in view of Johnson and rejected.
Claims 70 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Wohlford-Lenane et al. (Wohlford-Lenane, et al. Journal of virology 83.21: 11385-11390. (2009)) as evidenced by Schaal, et al. (Schaal, et al. PLoS One 12.11: e0187868 (2017)) as applied to claim 54 above, and further in view of Kumar et al. (Kumar, et al. New microbes and new infections 35: 100682 (2020)).
Regarding claim 70, claim 54 is anticipated as described above. Claim 70 further recites the case wherein claim 54 further comprises coadministration of the formulation with an antibody directed to the coronavirus.
The method of Wohlford-Leane and Schaal does not specifically disclose such an antibody. However, Kumar discloses the use of monoclonal antibodies against COVID-19, a coronavirus: “Chunyan Wang et al. were first to report that 47D11 (human) monoclonal antibody that neutralizes SARS-CoV-2. Research reports declaring that the 47D11 binds a conserved epitope on the spike receptor-binding domain and cross-neutralize SARS-CoV-2. The cross-reactive nature of 47D11 shows that the antibody is more possible to target the conserved core structure of the S1B receptor binding domain. Hence these neutralizing antibodies can reduce the course of virus action in the host or defend an uninfected host that is exposed to the virus.” (Kumar et al., page 3, col. 1, para. 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Wohlford-Leane and Schaal with the monoclonal antibody of Kumar to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to combine these therapeutics because they both are targeting the same virus type, coronaviruses. MPEP 2144.06(I) states: “"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).”
Similarly, a person of ordinary skill in the art would have a reasonable expectation of success because both therapeutics target coronaviruses. MPEP 2144.06(I) states: “"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).”
Consequently, claim 70 is obvious over Wohlford-Leane et al. as evidenced by Schaal et al. as applied to claim 54 above, further in view of Kumar et al. and rejected.
Regarding claim 71, claim 70 is obvious as described above. Claim 71 further recites the case wherein the antibody is selected from the group consisting of a convalescent serum and a therapeutic monoclonal antibody directed to the coronavirus.
As discussed above, Kumar discloses the usage of a monoclonal antibody.
Consequently, claim 71 is obvious over Wohlford-Leane et al. as evidenced by as applied to claim 54 above, further in view of Kumar et al. and rejected.
Claim 72 is rejected under 35 U.S.C. 103 as being unpatentable over Wohlford-Lenane et al. (Wohlford-Lenane, et al. Journal of virology 83.21: 11385-11390. (2009)) as evidenced by Schaal, et al. (Schaal, et al. PLoS One 12.11: e0187868 (2017)) as applied to claim 54 above, and further in view of Panoutsopoulos (Panoutsopoulos, Alexios A. Genes & Diseases 7.4: 528-534. (2020)) as evidenced by Wikipedia entry for Remdesivir (https://en.wikipedia.org/wiki/Remdesivir, accessed 2/7/2026).
Regarding claim 72, claim 54 is anticipated as described above. Claim 72 further recites the case wherein the method of claim 54 further comprises coadministration of a small molecule drug that is effective against the coronavirus, wherein the small molecule drug has a molecular weight of less than 1 kD.
The method of Wohlford-Leane and Schaal does not specifically disclose such a small molecule. However, Panoutsopoulos discloses the usage of remdesivir (MW 603 https://en.wikipedia.org/wiki/Remdesivir) against COVID-19, a coronavirus:
“In a letter to editor in Nature journal, M. Wang et al proved for the first time that remdesivir is highly effective in the control of COVID-19 infection in vitro, at a stage post virus entry.45 After that, many clinics start using remdesivir in a compassionate use for COVID-19 patients with severe symptoms, with the general feeling that it is helpful. Although, only with a randomized, unbiased trial, remdesivir could be used in as an official treatment for COVID-19.” (Panoutsopoulos, page 530, col. 2, para. 2).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method of Wohlford-Leane and Schaal with small molecule of Panoutsopoulos to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to combine these therapeutics because they both are targeting the same virus type, coronaviruses. MPEP 2144.06(I) states: “"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).”
Similarly, a person of ordinary skill in the art would have a reasonable expectation of success because both therapeutics target coronaviruses. MPEP 2144.06(I) states: “"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).”
Consequently, claim 72 is obvious over Wohlford-Leane et al. as evidenced by Schaal et al. as applied to claim 54 above, further in view of Panoutsopoulos and rejected.
Conclusion
No claim is allowed.
Claims 54-72 are objected to.
Claims 54-72 are rejected.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654