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 .
Status of Claims/Application
The preliminary amendment dated 02/02/2024 is acknowledged. Claims 1, and 5 – 14 are amended.
Claims 1 – 15 are currently pending and are examined on the merits herein.
Priority
Applicant's claim for the benefit of a prior-filed application under 35 U.S.C. 119(e)
or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The instant application is
a National Stage Application of PCT/EP2022/072074, filed on 08/05/2022, and claims priority to EP Application No. 21190172.3, filed on 08/06/2021, and EP Application No. 22185716.2, filed on 07/19/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted in the instant application
on 04/22/2024, 06/09/2025, 02/25/2026, and 07/17/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Hyperlinks are provided in several portions of the disclosure, pg. 1, line 23; pg. 2, line 9; pg. 3, line 1; pg. 3, line 27; pg. 4, line 22; pg. 15, line 25; pg. 16, line 4; and pg. 33, line 11. Appropriate correction is required.
The use of the term GlutaMax which is a trade name or a mark used in commerce, has been noted in this application. 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. Appropriate correction is required.
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.
Claim 2 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 2 recites the broad recitation “the administration is by oral, topical or injectable route”, and the claim also recites “preferably oral” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
Claims 1, and 6 are 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.
Claims 1, and 6 depend on claim 7, which is a later claim. Hence, claims 1, and 6 are not a proper dependent claims even though they include a further limitation. 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.
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 1, 6, 7, 13, and 14 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 treating a viral disease, does not reasonably provide enablement for preventing a viral disease or provide antiviral prophylaxis. 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.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the
experimentation should proceed to enable the determination of how to practice a
desired embodiment of the claimed invention. PPG V. Guardian, 75 F.3d 1558, 1564
(Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) The breadth of the claims,
2) The nature of the invention,
3) The state of the prior art,
4) The level of one of ordinary skill,
5) The level of predictability in the art,
6) The amount of direction provided by the inventor,
7) The existence of working examples, and
8) The quantity of experimentation necessary
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The breadth of the claims, the nature of the invention, and relative skill level
The invention relates to a method of treating or preventing a viral disease in an animal comprising administering to an animal a pharmaceutical composition of claim 7. In the absence of an explicit definition in Applicant's specification, the claims are given their broadest reasonable interpretation. See MPEP 2111. Taber's Cyclopedic Medical Dictionary (Venes, Donald, editor. "Prevention." Taber's Medical Dictionary, 25th ed., F.A. Davis Company, 2025. Taber's Online, www.tabers.com/tabersonline/view/Tabers-Dictionary/770284/all/prevention.) defines "prevention" as meaning, "The anticipation of harm, disease, or injury and the measures taken to block their effects." Taber's Cyclopedic Medical Dictionary (Venes, Donald, editor. "Prophylaxis." Taber's Medical Dictionary, 25th ed., F.A. Davis Company, 2025. Taber's Online, www.tabers.com/tabersonline/view/Tabers-Dictionary/762023/all/prophylaxis.) defines “prophylaxis” as meaning, “Observance of rules necessary to prevent disease.” In order to block the effects of a condition, the preventative agent must be completely effective. Therefore, in order to give the broadest reasonable interpretation to the claims, "prevention" or "prevent" are thus interpreted to mean the complete blocking of all symptoms or effects of a disorder or condition for an indefinite period of time in all population types (gender, age, etc.).
The claims are broad insofar as they recite preventing many types of viral diseases caused by porcine influenza virus, porcine rotavirus, feline infectious peritonitis virus, feline calcivirus, SARS-CoV-2, or coronaviridae virus. As described above, preventing indicates that any type of viral infection must never occur by administering the claimed pharmaceutical composition.
The relative skill of those in the art is high, that of an MD or PHD, someone with experience in viral infection.
The amount of direction or guidance provided and the presence or absence of working examples
The described examples (Examples 1 – 4) show that the claimed composition was effective in reducing the viral load of FIPV, FCV, porcine rotavirus A, and swine influenza virus but does not show that the viral infection was prevented. Furthermore, the disclosure and examples do not teach or suggest a method to predictably identify animals who would get a viral infection and then to further determine if the viral infection can be prevented by administering the claimed composition.
The state and predictability of the art
Turlewicz-Podbielska et al. (Porcine coronaviruses: overview of the state of the art, Virologica Sinica (2021) 36:833-851 (Published online: 15th March 2021)) (PTO-892)
The state of the prior art, discloses that like RNA viruses in general, coronaviruses (CoV) exhibit high mutation rates which, in combination with their strong tendency to recombine, enable them to overcome the host species barrier and adapt to new hosts. Rapid diagnosis is crucial for controlling CoV infections and preventing them from spreading (Abstract). CoV are responsible for a number of respiratory, digestive and nervous infections in mammals and birds. In pigs, the CoV causing gastrointestinal infections are the most important ones from a clinical and epidemiological standpoint (pg. 833, col. 1, para. 1). Six different CoV infecting pigs have been identified, including four belonging to the genus Alphacoronavirus transmissible gastroenteritis coronavirus
(TGEV), porcine respiratory coronavirus (PRCV), porcine epidemic diarrhea virus (PEDV) and swine acute diarrhea syndrome coronavirus (SADS-CoV)], one to the genus
Betacoronavirus porcine hemagglutinating encephalomyelitis virus (PHEV) and one to the genus Deltacoronavirus (PDCoV). Among them, TGEV, PRCV and PHEV have been circulating in pigs for decades, while PEDV, PDCoV and SADS-CoV are considered newly emerging CoV. In addition, chimeric TGEV and PEDV strains have been found in Italy, Germany, Slovakia and Spain (pg. 833, col. 2, para. 2). Chimeric swine enteric coronavirus (SeCoV), which is a novel recombinant between TGEV and PEDV, isolated in
Italy and Germany has a similar recombination pattern and 99.5% nucleotide identity (pg. 834, col. 1, para. 1). The appearance of a new CoV in humans, SARSCoV-2, which is attributed to zoonotic origin, holds interest of many scientists in the possibility of its occurrence and pathogenicity for domestic animals, including pigs as a host of different coronaviruses and one of the most important food-producing animals that has the potential to impact public health significantly. It has previously been found that a similar pathogen, SARS-CoV, responsible for SARS in humans, did not cause clinical symptoms or pathological lesions in pigs (pg. 834, col. 1, para. 1).
In the section on control and prevention, the state of the prior art teaches that a high level of biosecurity (strictly following the biosecurity rules) and in some cases vaccines are the first choice to prevent infection with these pathogens (pg. 846, col. 2, para. 2). There are two commercial vaccines based on a live modified TGEV strain for combined oral-intramuscular administration (PROSYSTEM® TGE/Rota; PROSYSTEM® TREC) (pg. 846, col. 2, para. 4). Live, inactivated and subunit PED vaccines have been developed in China, Japan, Korea and the US for sows, but their effectiveness is not sufficient to control PEDV outbreaks, since the disease has also appeared in vaccinated herds (Table 1). For PDCoV or SADS-CoV, there is currently no
information about the specific immunoprophylaxis (pg. 847, col. 1, para. 1).
Therefore, due to the constant emergence of new CoV, their enormous diversity, and their ability to shift host, there is incomplete information and difficulties to develop more effective methods to prevent transmission, and the preventive application against a viral disease using the claimed composition is highly unpredictable in the arts.
Ma, Wenjun (Swine influenza virus: current status and challenge, Virus Research 288:198118, 1 – 8, 2020) (IDS 07/17/2026).
Ma teaches that although large amount of swine influenza vaccines has been used in swine industry, swine influenza still cannot be efficiently controlled and has been an important economic disease for swine industry. The high diversity and varied distribution of different subtypes and genotypes of swine influenza viruses circulating in pigs globally is a major challenge to produce broadly effective vaccines and control disease. Importantly, swine influenza virus is able to cross species barrier to infect humans and even caused influenza pandemic in 2009 (Abstract). Ma teaches in the section on challenge to control swine influenza that live pigs are globally moving with increasing international trades, which has accelerated virus evolution and complicated swine influenza situations worldwide, and states that vaccination is the most efficient means to prevent and control influenza in humans and animals (pg. 5, col. 1, para. 2–3).
Therefore, this further confirms the difficulties to develop more effective methods to prevent transmission, and the preventive application against a viral disease using the claimed composition is highly unpredictable in the arts.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of a predictable method to identify animals who would develop these diseases without treatment, no one skilled in the art would accept the assertion that the instantly claimed agents could be predictably used to prevent a viral infection as inferred by the claim and contemplated by the specification. Furthermore, the quantity of experimentation to develop a method that could be used to prevent viral infection would be undue because a method to predictably identify an animal who would get a viral infection does not exist and as described above, one of ordinary skill would have to develop this method such that the claimed method could then be used as a preventative measure against the viral infection. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 7 is rejected under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by US 2020/0276219 (IDS 04/22/2024).
US’219 relates to certain N4-hydroxycytidine derivatives, pharmaceutical compositions, and methods related thereto. In certain embodiments, the disclosure relates to the treatment or prophylaxis of viral infections, such as Eastern, Western, and Venezuelan Equine Encephalitis (EEE, WEE and VEE, respectively), Chikungunya fever (CHIK), Ebola, Influenza, RSV, and Zika virus infection with the disclosed compounds (Abstract).
US’219 teaches β-D-N(4)-hydroxycytidine (EIDD-1931) (Fig. 1).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 7, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0276219 (IDS 04/22/2024).
The teachings of US’219 are as discussed in the 102 rejection above. US’219 further teaches methods of treating or preventing a viral infection caused by coronaviruses like MERS coronavirus, SARS coronavirus, and human coronavirus. US’219 exemplifies the N4-hyrdoxycytidine coronaviridae activity in Example 36 (pg. 102, col. 2, [0618]).
The teachings of US’219 differ from the instantly claimed invention in that US’219 does not teach the administration of the pharmaceutical composition comprising the antiviral nucleoside β-D-N(4)-hydroxycytidine or a prodrug or salt thereof and a pharmaceutically acceptable carrier to an animal, wherein the viral disease is caused by coronaviridae virus.
It would have been obvious to administer the pharmaceutical composition taught by US’219 to an animal suffering from a viral disease caused by coronaviridae virus before the effective filing date of the instantly claimed invention to treat the viral disease in the animal to arrive at the instantly claimed invention. One of ordinary skill in the art would be motivated to administer the composition of US’219, and would have a reasonable expectation of success as US’219 exemplifies the N4-hyrdoxycytidine coronaviridae activity in Example 36 (pg. 102, col. 2, [0618]).
Claims 1, 2, 4, 5, and 7 – 15 are rejected under 35 U.S.C. 103 as being unpatentable over US 2020/0276219 (IDS 04/22/2024) in view of Cook et al (A rational approach to identifying effective combined anticoronaviral therapies against feline coronavirus. 2021. bioRXiv 2020.07.09.195016) (PTO-892).
The teachings of US’219 are as discussed in the 102 rejection above. US’219 further teaches that the compound or pharmaceutical composition is administered orally, intravenously, or through the lungs, i.e., pulmonary administration (pg. 1, col. 2, [0013]). US’219 teaches that “Subject” refers any animal, preferably a human patient, livestock, or domestic pet (pg. 3, col. 1, [0048]). US’219 teaches that physiologically acceptable salts of the exemplary compounds are those that are formed internally in a subject administered compound for the treatment or prevention of disease ([0464]), and the exemplary compounds can be administered in the form of prodrugs. A prodrug can include a covalently bonded carrier which releases the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds ([0465]). US’219 teaches that the pharmaceutical compositions can be in a unit dosage form, and can be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which can be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use ([0466]), and can be administered as a single daily dose, divided over one or more daily doses ([0467]).
The teachings of US’219 differ from the instantly claimed invention in that US’219 does not teach the administration of the pharmaceutical composition comprising the antiviral nucleoside β-D-N(4)-hydroxycytidine or a prodrug or salt thereof and a pharmaceutically acceptable carrier to an animal, wherein the animal is a feline or a porcine to treat a viral disease or a viral infection caused by porcine influenza virus, porcine rotavirus, feline infectious peritonitis virus, feline calcivirus, or coronaviridae virus, or provide antiviral prophylaxis wherein the viral infection is selected from the group consisting of porcine influenza virus, porcine rotavirus, feline infectious peritonitis virus, or feline calcivirus.
Cook teaches that feline infectious peritonitis (FIP), caused by a genetic mutant of feline enteric coronavirus known as FIPV, is a highly fatal disease of cats with no currently available vaccine or FDA-approved cure. Cook states that they have screened 89 putative antiviral compounds and have identified 25 compounds with antiviral activity against FIPV, representing a variety of drug classes and mechanisms of antiviral action (Abstract). EIDD 1931 (β-D-N(4)-hydroxycytidine), and EIDD 2801 (prodrug of β-D-N(4)-hydroxycytidine) are among successful antiviral compounds. The antiviral efficacy (EC50) was determined for 10 antiviral compounds (pg. 8, Table 1), and for these compounds, the EC50 ranged from 0.04 µM to 13.47 µM. EC50 of EIDD 1931 is 0.09 µM. Cytotoxicity Safety Profiles (CSP) were determined for ten different antiviral compounds in CRFK (Crandell-Reese feline kidney) cells. Interestingly, based on the Promega CellToxTM Green Cytotoxicity Assay, the cytotoxicity of both EIDD compounds was essentially undetectable up to 100 µM. However, visual inspection of the EIDD treated wells just prior to fluorescent dye application and plate readings revealed differences in cell morphology (cytopathic effect) between untreated CRFK cells and treated cells. The untreated CRFK cells were characterized by adherent spindled morphology in a single monolayer, while the EIDD-treated wells demonstrated a clear decrease in confluency by comparison with variable cell morphology including rounding up of cells (cytopathic effect). The inconsistency between subjective visual assessment of EIDD-treated wells and the fluorescence assay is enigmatic. It is possible that the overall decreased cell number in EIDD-treated wells resulted in loss and degradation of nucleic acid necessary for fluorescence binding and detection in the CellTox assay (pg. 9 – 10). In the quantification of compound inhibition of viral RNA production with monotherapy, a real-time RT PCR assay was utilized to measure each antiviral compounds’ ability to inhibit coronaviral replication as monotherapy (viral RNA knock-down assay). Compounds demonstrating the greatest inhibition of FIPV RNA production were GC376, a 3C-like coronavirus protease inhibitor, GS-441524, EIDD-1931 and EIDD-2801, the latter three all being nucleoside analogs (Fig. 5, Table 3) (pg. 11 – 12). FIPV infected CRFK cells were incubated for 24 hours with compounds identified to possess anti-FIPV activity. Viral copy number was subsequently determined via RT-qPCR and normalized to feline GAPDH copy number to determined fold decrease effect for each compound. All compounds were tested at 10 µM unless otherwise specified. All experimental treatments were performed in triplicate wells and fold decrease calculated by dividing the average experimental, normalized FIPV copy number by the average normalized FIPV copy number determined for untreated, FIPV-infected wells (pg. 12).
It would have been obvious to combine US’219 and Cook before the effective filing date of the claimed invention by administering the pharmaceutical composition taught by US’219 comprising of β-D-N(4)-hydroxycytidine to a cat suffering from a viral disease or viral infection caused by feline infectious peritonitis virus as Cook teaches that β-D-N(4)-hydroxycytidine exhibits antiviral activity against FIPV to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to administer the pharmaceutical composition of US’219 to a feline because Cook teaches that β-D-N(4)-hydroxycytidine and its prodrug are among the compounds that exhibit the greatest inhibition of FIPV RNA production (pg. 11). One of ordinary skill in the art would have a reasonable expectation of success as Cook teaches that the antiviral efficacy (EC50) of β-D-N(4)-hydroxycytidine was found to be 0.09 µM (pg. 8).
Regarding claim 11, as Cook teaches that the EC50, the half maximal effective concentration of EIDD1931 is 0.09 µM, and that of EIDD 2801 is 0.4 µM, and the fold reduction in viral RNA copy number for EIDD-1931 is 3,700 and for EIDD-2801 is 2,110, the claim limitation “the antiviral response is the amount of virus is substantially eliminated” is met. The claim limitation “the amount of virus is substantially eliminated” is interpreted to mean a reduction of 50% or more of the viral load.
Claims 1 – 3, 5, and 7 – 13 are rejected under 35 U.S.C. 103 as being unpatentable over Yoon et al (Orally efficacious broad-spectrum ribonucleoside analog inhibitor of influenza and respiratory syncytial viruses, 2018, Antimicrobial Agents and Chemotherapy, 62(8):e00766-18, 1-18) (IDS 04/22/2024).
Yoon teaches that by using a dual-pathogen high-throughput screening protocol for influenza A virus (IAV) and RSV inhibitors, N4-hydroxycytidine (NHC) had been identified as a potent inhibitor of RSV, influenza B viruses, and IAVs of human, avian, and swine origins. The compound was orally efficacious against RSV and both seasonal and highly pathogenic avian IAVs in mouse models, reducing lung virus loads and alleviating disease biomarkers. Oral dosing reduced IAV burdens in a guinea pig transmission model and suppressed virus spread to uninfected contact animals through direct transmission. Based on its broad-spectrum efficacy and pharmacokinetic properties, NHC is a promising candidate for future clinical development as a treatment option for influenza-like diseases (Abstract). Focusing on the dual-active compounds only, EIDD-1931 or N4-hydroxycytidine [NHC]) (Fig. 1B) showed active concentrations in the nanomolar to low-micromolar range and selectivity indices (SIs) (SI = CC50 [50% cytotoxic concentration]/EC50 [50% effective concentration]) of ≥89 against a broad panel of RSV, IAV, and IBV laboratory strains and isolates (Table 1). This group included clinical RSV isolates cultured from nasal wash specimens (Fig. 1C); IAVs of human, avian, and swine origins representing both group 1 and 2 hemagglutinins (HAs) (Fig. 1D and Table 1); highly pathogenic H5N1 and emerging H7N9 avian IAVs (AIVs) (Fig. 1E); and IBVs representing both circulating lineages (35), Victoria and Yamagata (Fig. 1F). Drug combination testing of NHC and the current standard of care (SOC) against IAV infection, oseltamivir, in cultured cells identified an extended plateau area of medium-level antiviral synergy (HSA model), while no significant increase in cytotoxicity was noted in the presence of the drug combination (Fig. S3). These data demonstrate the activity of NHC against a panel of respiratory viruses associated with influenza-like diseases. Combined with the previously reported antiviral activity of NHC in cell culture against some Flaviviridae, Coronaviridae, and Togaviridae family members, these data establish the broad-spectrum activity of the compound against different positive- and negative-strand RNA virus families and, in the case of IAV infection, spotlight the potential for synergistic combination with the current SOC (pg. 3).
The teachings of Yoon differ from the instantly claimed invention in that Yoon does not exemplify the administration of a pharmaceutical composition comprising β-D-N(4)-hydroxycytidine to a porcine suffering from a viral disease or a viral infection caused by porcine influenza virus.
It would have been obvious to administer a pharmaceutical composition comprising NHC or its prodrug as taught by Yoon before the effective filing date of the claimed invention to a porcine suffering from a viral disease or viral infection caused by porcine influenza virus as Yoon teaches that β-D-N(4)-hydroxycytidine exhibits antiviral activity against many influenza viruses including those of swine origin to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to administer the pharmaceutical composition comprising NHC or its prodrug to a porcine because Yoon teaches that β-D-N(4)-hydroxycytidine shows activity in the nanomolar to low-micromolar range against a broad panel of RSV, IAV, and IBV laboratory strains and isolates (pg. 3). One of ordinary skill in the art would have a reasonable expectation of success as Yoon teaches that their data establish the broad-spectrum activity of the compound against different positive- and negative-strand RNA virus families and, in the case of IAV infection, spotlight the potential for synergistic combination with the current standard of care (pg. 3).
Claims 6, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Painter et al (Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity against SARS-CoV-2, 2021, Antimicrobial Agents and Chemotherapy, 65(5):e02428-20, 1-14) (IDS 04/22/2024).
Painter teaches that molnupiravir (EIDD-2801/MK-4482), the prodrug of the active antiviral ribonucleoside analog β-D-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and seasonal and pandemic influenza viruses. Single and multiple doses of molnupiravir were evaluated in this first-inhuman, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics, and molnupiravir was well tolerated (Abstract). Painter teaches that the ability of molnupiravir to potentially treat highly pathogenic respiratory RNA virus infections has been demonstrated in ferret models of disease. In ferrets, molnupiravir was highly effective at treating seasonal and pandemic influenza infections and in blocking SARS-CoV-2 transmission, and molnupiravir was also highly effective when administered prophylactically and therapeutically in mouse models of SARS-CoV-2 and MERS-CoV. (pg. 12). Very little molnupiravir or EIDD-1931 was detected in urine, despite the fact that nucleoside analogs as well as natural nucleosides are in general actively secreted by the kidney. This may be the result of metabolism of EIDD-1931 to cytidine and uridine. Molnupiravir was well tolerated, and no subjects experienced serious adverse events (pg. 12).
The teachings of Painter differ from the instantly claimed invention in that Painter does not exemplify the administration of the pharmaceutical composition comprising NHC or a prodrug to an animal suffering from a viral disease caused by SARS-CoV-2, wherein the animal is a swine, a bovid, a horse, a dog or a cat.
It would have been obvious to administer the pharmaceutical composition comprising of β-D-N(4)-hydroxycytidine or a prodrug taught by Painter before the effective filing date of the claimed invention to a swine, a bovid, a horse, a dog or a cat suffering from a viral disease resulting from a SARS-CoV-2 infection as Painter teaches molnupiravir, a prodrug of β-D-N(4)-hydroxycytidine was highly effective in ferrets, mouse and human subjects indicating that it would be effective in other mammals also, to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to administer the pharmaceutical composition comprising of β-D-N(4)-hydroxycytidine or a prodrug to a swine, a bovid, a horse, a dog or a cat because Painter teaches that molnupiravir was also highly effective when administered prophylactically and therapeutically in mouse models of SARS-CoV-2 and MERS-CoV (pg. 12). One of ordinary skill in the art would have a reasonable expectation of success as Painter teaches that molnupiravir is well absorbed after oral administration and absorption is minimally affected by food intake, and molnupiravir was well tolerated, and no subjects experienced serious adverse events (pg. 12).
Conclusion
Claims 1 – 15 are rejected. No claims are allowed.
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/J.A.M./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693
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