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 .
Claims 1-23, and 26-46, submitted on 27 March 2023, represent all claims currently under consideration.
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.
Priority
This application is a 371 of PCT/US2021/054049, filed 7 October 2021, which claims priority to provisional US 63/089,288, filed 8 October 2020. The effective filing date is 8 October 2020.
Information Disclosure Statement
Two Information Disclosure Statements (IDSs), submitted on 27 March 2023 and 27 September 2023, are acknowledged and have been considered.
Specification
The use of the term ACICLOVIR, AGENRASE, and VALTREX, which are trade names or marks used in commerce, has been noted in this application (Paragraph 0046). The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim46 is objected to because of the following informalities: There is a repeated structure within the Markush list of compounds:
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. Is found on Page 20, and
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is found on Page 21. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
Claim 23 is 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. Factors to be considered
in making the determination as to whether one skilled in the art would recognize that
applicant was in possession of the claimed invention as a whole at the time of filing include : (a) Actual reduction to practice; (b) Disclosure of drawings of structural
chemical formulas; (c) Sufficient identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional
characteristics when coupled with a known or disclosed correlation between function
and structure; (d) Method of making the claimed invention; (e) Level of skill and
knowledge in the art and (f) Predictability in the art. While all of these factors are
considered, a sufficient number for a prima facie case are discussed below:
Claim 23 claims the method of treating viral infections of claim 1, in combination with at least one additional anti-viral therapeutic, and states that this therapeutic can be a fusion inhibitor, integrase inhibitor, protease inhibitor, reverse transcriptase inhibitor, or synergistic enhancer. The specification does not define these compounds, nor does the specification provide a representative drug or class of compounds which the artisan would be able to use in the practice of the invention as claimed. There is no core structure defined which provides the basis for the breadth of the claim. The artisan can only determine what constitutes an anti-viral drug in each of these categories from a posteriori testing and analysis, and would not know prior to utilizing a compound if it will function in the invention as claimed. The artisan would generally understand what each of the classes of compounds functionally does, but without specific guidance from the specification as to what compounds or classes of compounds can perform these functions, there would be no expectation of predictability for practicing this invention. Thus, there is no support in the specification that applicant was in possession of the claimed invention as a whole at the time of filing.
Claim Rejections - 35 USC § 112(b)
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 1-23, 26-38, and 43-45 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. Claim 1 states that variables R1 and R1’ can be a C1 alkenyl or C1 alkynyl, which is not possible as an alkenyl or alkynyl requires two carbons for the bond to form. 2-23, 26-38, and 43-45 are similarly rejected because they do not resolve the indefinite issue of the parent rejected claim.
Claim 1 is 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. Claim 1 recites the limitation "provided that one of R1 and R1’ is OH or R1 and R1’ together are =O" in Line 10. There is insufficient antecedent basis for this limitation in the claim as the claim has not stated prior to this that variable R1 or R1’ can be OH or =O. Claims 2-23 and 26-46 are similarly rejected because they do not resolve the indefinite issue of the parent rejected claim.
Claim 46 is 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. Claim 46 depends on Claim 1, which recites the limitation "provided that one of R1 and R1’ is OH or together are =O. Claim 1 does not state that variable R1 or R1’ can be =N. Two compounds of Claim 46 contain a =N moiety, and lack an -OH or =O for R1 or R1’. There is insufficient antecedent basis for this limitation in the claim.
Claim 23 is 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. Claim 23 contains multiple trademark/trade names including NEXAVIR, AMPLIGEN, ARBIDOL, ATRILPA, BICTARVY, COMBIVIR, DESCOVY, IMUNOVIR, NORVIR, TRIZIVIR, and TRUVADA. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe various anti-viral drug formulations and, accordingly, the identification/description is indefinite. The claim also contains reference to ACICLOVIR which does not have proper notation for a trademark. The Examiner suggests removing each trademark from the claim and replacing with the appropriate generic terminology.
Claim 23 is 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. Claim 23 claims the use of an anti-viral therapeutic which includes “fusion inhibitor”, “integrase inhibitor ”, “nucleoside analogs”, “protease inhibitor (pharmacology)”, “reverse transcriptase inhibitor”, or “synergistic enhancer (antiretroviral)”. Neither the claim nor the specification defines the metes and bounds of these classes of compounds, causing their definitions to be indefinite, rendering the claim indefinite.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 46 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The compounds of Claim 46 contain moieties which are not claimed in Claim 1, such as
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. Claim 1 does not state that variable R1 can be (=N), causing Claim 46 to be broader than Claim 1. Claim 1 also states that one of variable R1 and R1’ must be -OH or =O, and this is not the case. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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.
Claims 1-7, 11-13, 26, 29-32, 39, 43 and 44 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Iwamoto (Biochemical and Biophysical Research Communications, 443, 2014, 808-813).
Iwamoto describes two compounds (Described in Section 2.1 Reagents, 22(S)-Hydroxycholesterol and 20α-hydroxycholesterol)), shown below for applicants’ convenience. In these compounds, the following definitions apply against the examined variables: (R1, R1’) are (OH, H) or (Me, OH); R2-R5, R7 and R8 are each H; R6 is CH2-isopropyl.
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These compounds are used as hepatitis B viral entry inhibitors in vitro (abstract). The authors established a strain of HepG2 cells engineered to overexpress the human NTCP gene, and were shown to be susceptible with infection by blood-borne and cell-culture derived hepatitis B virus (HBV). Knockdown analysis suggested that HBV infection was mediated by NTCP. HBV infection was blocked by an anti-HBV surface protein neutralizing antibody, by compounds known to inhibit NTCP transporter activity, and by cyclosporin A. This method is used to inhibit entry of Hepatitis B, which is a member of the Hepadnaviridae family of viruses, and is a DNA virus.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7, 11-12, 18-23, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Parhami (WO 2011/103175; Publication Date: 25 August 2011) in view of Liu (Journal of Lipid Research, 59, 2018).
Parhami discloses compositions containing oxysterol compounds represented by formula I or Formula II, e.g., comprising one or more of Oxy 16, Oxy 22, Oxy 30, Oxy 31, Oxy 35, Oxy 37, Oxy 43, Oxy 44, Oxy 45, or Oxy 47. The compounds are shown to act as agonists for liver X receptor (Abstract). Liver X receptors are members of the family of nuclear hormone receptors and are involved in a variety of physiologic processes including anti-inflammatory signaling (Page 2, Lines 4-5). As used herein, a liver X receptor (LXR) agonist is a compound that stimulates LXRα, LXRβ or both. An LXR agonist is a chemical or biological substance that can bind to a receptor and trigger a response in a particular type of cell (Page 6, Lines 28-31). A pharmaceutical composition of the invention can contain other pharmaceuticals (Page 13, Lines 18-19). The LXR agonists of the invention, alone or in combination with other therapeutic agents, can be made into aerosol formulations to be administered via inhalation (Page 14, Lines 13-15). Specific compounds of the invention include
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(Pages 19-20). These compounds have variable R1’ as methyl, R1 as OH, variable R7 as H, variables R2, R3, R4, and R5 as hydrogen, and variable R6 as alkyl, phenyl, substituted phenyl, and heteroaryl. Table 1 (Page 21) lists the effect of oxysterol compounds on expression of LXR target gene ABCA1 relative to housekeeping gene, with Oxy16 having a 2.1 fold induction, Oxy22 having a 2.2 fold induction, Oxy43 having a 2.5 fold induction, Oxy44 having a 2.5 fold induction, Oxy45 having a 3.5 fold induction, and Oxy47 having a 1.8 fold induction, providing a motivation for selecting these compounds, and a reasonable expectation of success in their selection.
Parhami does not disclose methods for treating viral infections, or inhibiting cellular viral entry.
. Liu studied the role of 25-hydroxycholesterol in viral infections. The production of 25-hydroxycholesterol (25HC), a potent inhibitor of viral infection, is catalyzed by cholesterol 25-hydroxylase (C25H). 25HC induces CH25H expression in a liver-X receptor (LXR)-dependent manner, implying that LXR can play an important role in antiviral infection. The authors determined that activation by LXR by 25HC or synthetic ligands inhibited infection of herpes simplex virus type-1 (HSV-1) or MLV-(VSV)-GFP in HepG2 cells or RAW 264.7 macrophages. Genetic deletion of LXRα, LXRβ, or CH25H expression increased cell susceptibility to HSV-1 infection and attenuated the inhibition of LXR on viral infection. The expression of CH25H was inversely correlated to cell susceptibility to viral infection and the antiviral actions of LXR. Administration of the synthetic LXR agonist T317 to BALB/c mice reduced HSV-1 growth in mouse tissues. Taken together, the results demonstrate an antiviral system of 25HC involvement with LXR activation, interaction between CH25H and IFN-gamma, and 25HC metabolism (Abstract).
Parhami and Liu are considered analogous to the claimed invention as all are involved in the use of oxysterols for the treatment of disease. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to apply the oxysterol LXR agonists of Parhami for the treatment of the viral infections such as hepatitis B as taught by Liu. Liu demonstrates that LXR agonism results in antiviral activity, and as the compounds of Parhami are LXR agonists, the artisan would recognize that they can be substituted in to the methods of Liu (See MPEP § 2143 I (B)). The artisan would be motivated to, and have a reasonable expectation of success, as the data provided by Parhami shows these compounds induce expression of the LXR target gene ABCA1, indicating their potent agonism of LXR.
Regarding Claims 21-23, as the compounds disclosed by Parhami are known to possess antiviral activity, it would be prima facie obvious to one of ordinary skill in the art to combine this treatment with other known anti-viral compounds as each are known individually to be useful for the treatment of viral infections (See MPEP § 2144.06 I) "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).
Claims 1-7, 11-13, 18-23, 26-32, 43, 44, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Iwamoto (Biochemical and Biophysical Research Communications, 443, 2014, 808-813).
As described previously, Iwamoto teaches the treatment of hepatitis B viral infections using oxysterols which meet the limitations of compounds claimed in the examined application.
Iwamoto fails to disclose systemic administration, local administration, administration with an additional anti-viral therapeutic, or treatment in vivo. However, it would be prima facie obvious to one of ordinary skill in the art to formulate the oxysterols for the treatment of HBV viruses in a manner for local administration to the site of infection (the liver), and for systemic delivery. Moreover, as these compounds are known to possess antiviral activity, it would be prima facie obvious to one of ordinary skill in the art to combine this treatment with other known anti-viral compounds as each are known individually to be useful for the treatment of viral infections (See MPEP § 2144.06 I) "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).
Regarding Claims 43, 44 and 46, 20α-hydroxycholesterol is a stereoisomer of
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. The artisan would not expect these compounds to have significantly different activity compared to one another due to the close chemical structure (See MPEP § 2144.09 I). 20α-hydroxycholesterol is shown to have antiviral activity, and the artisan would not expect this stereoisomer to have significantly different activity.
Claims 1-6, 8, 9, 11-12, 14-16, 18-23, 26-31, 43, 44 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Iwamoto (Biochemical and Biophysical Research Communications, 443, 2014, 808-813) in view of Marcello (Redox Biology, 36, 2020, 101682, Available online: 10 August 2020).
As described previously, Iwamoto teaches the treatment of hepatitis B viral infections using oxysterols which meet the limitations of compounds claimed in the examined application.
Iwamoto does not teach the treatment of RNA viruses using oxysterol compounds.
Marcello teaches the inhibitory activity of oxysterols against the SARS-CoV-2 virus. The authors report on the in vitro inhibitory activity of the redox active oxysterol 27-hydroxycholesterol against SARS-CoV-2 and against one of the common cold agents HCoV-OC43 human coronavirus without significant cytotoxicity. The exogenous administration of 27-hydroxycholesterol may represent in the near future a valid antiviral strategy in the worsening diseases caused by present and emerging coronaviruses (Abstract).
Iwamoto and Marcello are considered analogous to the claimed invention as all are involved in the treatment of viral infections using oxysterols. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to utilize the oxysterols of Iwamoto for the treatment of coronavirus infections such as SARS-CoV-2. Marcello demonstrates that the oxysterol 27-hydroxycholesterol possesses antiviral activity towards SARS-Cov-2. The artisan would have a reasonable expectation of success in applying the oxysterols of Iwamoto for the treatment of this viral infection as these active compounds all belong to the same chemical class (steroids, and more specifically, oxysterols) (See MPEP § 2144.09 I). The use of the antiviral oxysterols of Iwamoto for the treatment of SARS-CoV-2 is prima facie obvious simple substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)); Iwamoto discloses the antiviral activity of two oxysterols, while Marcello discloses the anti-SARS-CoV-2 activity of a similar oxysterol, and the artisan would recognize that the oxysterols of Iwamoto could be substituted into this method and predictably result in an anti-SARS-CoV-2 treatment.
Iwamoto and Marcello fail to disclose systemic administration, local administration, administration with an additional anti-viral therapeutic, or treatment in vivo. However, it would be prima facie obvious to one of ordinary skill in the art to formulate the oxysterols in a manner for local administration to the site of infection (the lungs) and for systemic delivery. Moreover, as these compounds are known to possess antiviral activity, it would be prima facie obvious to one of ordinary skill in the art to combine this treatment with other known anti-viral compounds as each are known individually to be useful for the treatment of viral infections (See MPEP § 2144.06 I) "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).
Regarding Claims 43, 44, and 46, 20α-hydroxycholesterol is a stereoisomer of
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. The artisan would not expect these compounds to have significantly different activity compared to one another due to the close chemical structure (See MPEP § 2144.09 I). 20α-hydroxycholesterol is shown to have antiviral activity, and the artisan would not expect this stereoisomer to have significantly different activity.
Claims 1-6, 8, 9, 11-12, 17-23, 26-31, 43, 44 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Iwamoto (Biochemical and Biophysical Research Communications, 443, 2014, 808-813) in view of Moog (Antiviral Chemistry and Chemotherapy, 9, 491-496, 1998).
As described previously, Iwamoto teaches the treatment of hepatitis B viral infections using oxysterols which meet the limitations of compounds claimed in the examined application.
Iwamoto fails to teach the treatment of HIV infections using oxysterols.
Moog (See IDS, 27 March 2023) investigated oxysterols, oxygenated derivatives of cholesterol, for their anti-human immunodeficiency virus (HIV) activity in vitro. The three oxysterols tested were 7β-hydroxycholesterol (7β-OHC), 25-hydroxylcholesterol (25-OHC), and 7β,25-dihydroxycholesterol (7,25-OHC). The selectivity indexes for 7β-OHC and 25-OHC are quite modest, while the 7,25-OHC exhibited antiviral properties at concentrations 13- to 25-fold lower than the highest concentration tested at which no toxicity was measured. Oxysterols are naturally occurring compounds and the authors speculate that they are relevant in the treatment of HIV-infected individuals (Abstract). HIV like other retroviruses, has a lipid envelope containing particularly high amounts of cholesterol, inhibitors of cholesterol biosynthesis, and compounds that alter membrane fluidity have been proposed as alternative therapeutic agents for AIDS treatment. Consequently, the authors investigated the effects of oxygenated derivatives of cholesterol on the replication of HIV in vitro, demonstrating that the three oxysterols which were tested were able to inhibit HIV production in human T cell lines and human PBMCs (Introduction).
Iwamoto and Moog are considered analogous to the claimed invention as all are involved in the treatment of viral infections using oxysterols. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to utilize the oxysterols of Iwamoto for the treatment of infections by HIV. Moog demonstrates that three structurally similar oxysterols are capable of inhibiting HIV replication in vitro. The artisan would have a reasonable expectation of success in applying the oxysterols of Iwamoto for the treatment of this viral infection as these active compounds all belong to the same chemical class (steroids, and more specifically, oxysterols) , which are shown to possess antiviral activity of their own (See MPEP § 2144.09 I). The use of the antiviral oxysterols of Iwamoto for the treatment of HIV is prima facie obvious simple substitution of one known element for another to obtain predictable results (See MPEP § 2143 I (B)); Iwamoto discloses the antiviral activity of two oxysterols, while Moog demonstrates that three structurally similar oxysterols are capable of inhibiting HIV replication, and the artisan would recognize that the oxysterols of Iwamoto could be substituted into this method and predictably result in a method for the inhibition of HIV replication and growth as these compounds are each steroids, and more specifically, oxysterols.
Iwamoto and Moog fail to disclose systemic administration, local administration, administration with an additional anti-viral therapeutic, or treatment in vivo. However, it would be prima facie obvious to one of ordinary skill in the art to formulate the oxysterols in a manner for local administration to the site of infection and for systemic delivery. Moreover, as these compounds are known to possess antiviral activity, it would be prima facie obvious to one of ordinary skill in the art to combine this treatment with other known anti-viral compounds as each are known individually to be useful for the treatment of viral infections (See MPEP § 2144.06 I) "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).
Regarding Claims 43, 44 and 46, 20α-hydroxycholesterol is a stereoisomer of
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. The artisan would not expect these compounds to have significantly different activity compared to one another due to the close chemical structure (See MPEP § 2144.09 I). 20α-hydroxycholesterol is shown to have antiviral activity, and the artisan would not expect this stereoisomer to have significantly different activity.
Claims 1-23, 26-38, and 43-46 are rejected under 35 U.S.C. 103 as being unpatentable over Parhami (WO 2011/103175; Publication Date: 25 August 2011) in view of Liu (Journal of Lipid Research, 59, 2018), Iwamoto (Biochemical and Biophysical Research Communications, 443, 2014, 808-813), Moog (Antiviral Chemistry and Chemotherapy, 9, 491-496, 1998), Marcello (Redox Biology, 36, 2020, 101682, Available online: 10 August 2020), and Lembo (Molecular Aspects of Medicine, Volume 49, 2016, 23-30).
The teachings of Parhami, Liu, Iwamoto, Moog, and Marcello are described previously and are fully incorporated into this rejection.
Lembo provides a review of oxysterols and their antiviral activity against non-enveloped and enveloped human viral pathogens (Abstract). Table 1 lists the antiviral activity of several oxysterols. 25-hydroxysterol demonstrating activity against HIV, vesicular stomatitis virus (VSV), murid herpes virus 68 (MHV68), Ebola virus (EboV), Rift Valley fever virus (RVFV), Russian Spring summer encephalitis virus (RSSEV), herpes simplex virus (HSV), Nipah virus, influenza virus, varicella zoster virus (VZV), murine cytomegalovirus (MCMV), hepatitis C virus (HCV), hepatitis B virus (HBV), poliovirus, encephalomyocarditis virus (EMCV), human papillomavirus type 16 (HPV-16), human rotavirus (HRoV), and human rhinovirus (HRhV). 27-hydroxycholesterol has activity against HPV-16, HRoV, HRhV, MCMV, and HSV-1. 24-hydroxycholesterol showed activity against MCMV and HSV-1. 7β-hydroxycholesterol was active against HIV and HBV. 7β,25-dihydroxycholesterol was active against HIV. 25-epoxycholesterol was active against MCMV. 22(S)-hydroxycholesterol and 20α-hydroxycholesterol have activity against HBV.
Parhami, Liu, Iwamoto, Moog, Marcello, and Lembo are considered analogous to the claimed invention as all are involved in the treatment of viral infections using oxysterols. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to utilize the oxysterols of Parhami for the treatment of the various viral infections which have been shown to be sensitive to treatment by oxysterols. The compounds of Parhami are oxysterols, which are active on the LXR, which Liu demonstrates plays an important role in antiviral activity in the body. Iwamoto, Moog, Marcello, and Lembo demonstrate that structurally similar oxysterols possess antiviral activity against DNA, positive sense, and negative sense RNA viruses. The use of the oxysterols of Parhami for the treatment of the claimed viruses is prima facie obvious combination of prior art elements according to known methods to yield predictable results (See MPEP § 2143 I (A)); the oxysterols of Parhami are LXR agonists, which Liu shows is a key pathway in the antiviral response of the body. Structurally similar oxysterols are shown to possess antiviral activity, and as such, the artisan would have reasonable expectation of success in applying these compounds for the treatment of viral infections.
Regarding Claims 29-31, 33-36, 43, 44 and 46, the compounds Oxy16, Oxy22, Oxy43, Oxy44, Oxy45, and Oxy47 are stereoisomers of the compounds of the examined application, and as such, the artisan would not expect these compounds to have significantly different activities or properties than what is claimed (See MPEP § 2144.09 I). Because the stereoisomers of what is claimed is shown to have antiviral activity, the artisan would not expect the claimed compounds to have significantly different activity than what is disclosed in the prior art.
Regarding Claims 32, 37, 38, and 45-46, the compounds Oxy16, Oxy22, Oxy43, Oxy44, Oxy45, and Oxy47 are stereoisomers of these compounds, and differ by the inclusion of a double bond. The artisan would not expect these compounds to have significantly different activities or properties than what is claimed due to the close structural similarity (See MPEP § 2144.09 I).
The cited references fail to disclose administration with an additional anti-viral therapeutic. However, as these compounds are known to possess antiviral activity, it would be prima facie obvious to one of ordinary skill in the art to combine this treatment with other known anti-viral compounds as each are known individually to be useful for the treatment of viral infections (See MPEP § 2144.06 I) "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).
Allowable Subject Matter
Claims 39-42 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
The following is an examiner’s statement of reasons for allowance: The oxysterols of Parhami and Iwamoto do not have a hydrogen at the R1 position, and all contain a hydroxyl group and methyl moiety. There is no teaching, suggestion, or motivation found in the work of Parhami, Iwamoto, or the other cited art to modify the compounds of Parhami or Iwamoto to remove the hydroxyl or methyl moieties and replace with a hydrogen atom, and there would further be no reasonable expectation of success in performing this modification. A search of the prior art retrieved no compounds which contain these modifications (See STN Search, Search Notes).
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 1-23 and 26-46 are rejected.
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/P.M.R./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625