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 . 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
The instant application is a 371 of PCT/EP2022/080430 filed on 11/01/2022 and claims foreign priority to EP21205795.4 filed on 11/01/2021. The certified copy of the foreign priority application filed on 04/29/2024 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/29/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
The preliminary claim amendments filed on 04/29/2024 is acknowledged. Claims 1-12 are amended. Claims 13-20 are newly added.
Accordingly, claims 1-20 are pending and being examined on the merits herein.
Claim Objections
Claim 19 is objected to because of the following informalities:
The “whereinn” recited in claim 19 is misspelled and should be spelled “wherein”
Appropriate correction is required.
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 14-15 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.
Claims 14-15 recite “wherein the disease is a moderate to severe case of the disease”.
The limitation “moderate to severe case” is a term of degree, and the specification does not does not provide a definition or a standard for determining a moderate to severe case of the recited disease. Therefore, the ordinary skilled artisan cannot ascertain the scope of the claims, rendering these claims indefinite.
For purposes of compact prosecution, the recited “moderate to severe case of the disease” is being interpreted as having severe symptoms of a disease caused by SARS-CoV-2 and/or COVID-19 such as severe respiratory diseases.
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.
Claims 19-20 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.
Claim 19 recites “The method of claim 18, wherein the single stranded RNA virus I selected from HCoV-229E, HCoV-NL63, or a betacoronavirus”. Claim 20 recites “The method of claim 19, wherein the beta coronavirus is selected from HCoV-OC43, SARS-CoV-1, HCoV-HKU1, MERS-CoV, or SARS-CoV-2”.
Claims 19-20 depend from claim 18, and claim 18 depends from claim 13. Claim 18 recites “The method of claim 13, wherein the RNA virus is a single stranded RNA virus”, and claim 13 recites “wherein the RNA virus is HIV, HCV, Ebola, rotavirus, Zika virus, polio virus, rhinovirus, hepatitis A virus, measles virus, mumps virus, RSV, rabies, Lassa virus, hantavirus, or influenza”.
Claims 19-20 fail to include all the limitations of the claims upon which it depends because claims 13 and 18 do not include the single stranded RNA virus species recited in claim 19 or the betacoronavirus species recited in claim 20.
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 § 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.
Claims 1-10 13-14, and 16-20 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 recited disease, does not reasonably provide enablement for preventing a recited disease. 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 nature of the invention, the breadth of the claims, and relative skill level
The invention relates to a method of preventing and/or treating a disease in a mammalian subject in need thereof, comprising administering to the mammalian subject a compound according to the recited Formula (l) structure, or a tautomer, solvate or pharmaceutically acceptable salt thereof.
The claims are broad in that they encompass a method of prevent any disease in a mammalian subject.
In the absence of an explicit definition in Applicant’s specification, the claims are given their broadest reasonable interpretation (See MPEP 2111). Institute for International Medical Education (IIME, reference included with PTO-892), defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (see page 16, “Prevention”). IIME further states that “Primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe. Secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health. Tertiary prevention consists of the measures available to reduce or eliminate long-term”.
Therefore, in order to give the broadest reasonable interpretation to the claims, “prevention” or "prevent" are thus interpreted to mean that the onset of a condition never occurs and the patient’s health is protected and preserved.
The relative skill of those in the art is high, that of an MD or PHD, someone with experience in the recited conditions/diseases.
The amount of direction or guidance provided and the presence or absence of working examples
Applicant has demonstrated in Examples 101-103 that administering the Formula (l) compound with the first DHODH inhibitor compound in instant claim 8 produced a synergistic therapeutic effect against SARS-CoV-2, HRV-14, influenza A, and RSV.
Applicant demonstrates in FIG. 1 that the combination at 1x to 4x EC50 dosages produced a synergistic viral inhibition effect in a SARS-CoV-2 inhibition assay.
Applicant further demonstrates in the second table on page 26 that a combination of 25 micromolar of the Example 50 compound (first DHODH compound in instant claim 8) with 0.0079 to 25 micromolar of the Example 1 compound (the instant Formula (l) compound) resulted in antiviral synergy against RSV. Applicant also appears to demonstrate in the third table on page 26 the same synergy effect against HRV-14 virus.
However, the instant disclosure does not identify a method that could be used by one of ordinary skill in the art to determine that a subject would have predictably developed a disease without the claimed methods in order to establish that the disease was prevented.
The described example suggests that the recited Formula (l) and DHODH inhibitor was effective in treating viral infections. However, the example does not demonstrate prevention of a disease or a predictable method to identify patients who would have developed a disease.
The state and predictability of the art
There are no art recognized methods that could be used to establish that a disease was prevented using therapeutic treatment or to identify patients who would predictably develop a disease in order to predictably identify that prevention was achieved using therapeutic approaches. Rather, the art indicates that identifying patients who would develop a disease was not predictable.
For example, McArthur (in PTO-892) teaches emerging infectious diseases and further teaches that new infections could be the result of changes or evolution of existing organisms, known infections spreading to new geographic areas or populations, previously unrecognized infections appearing in areas undergoing ecologic transformation, or old infections reemerging because of antimicrobial resistance in known agents or breakdowns in public health measures. Emerging infections account for at least 15% of all human pathogens and are a major concern and can be zoonotic, synoptic, foodborne, vector-borne, or airborne. Regardless, for an infectious disease to become established, the infectious agent must be introduced into a vulnerable population and have the ability to spread (abstract). McArthur teaches that infectious diseases are inevitable and unpredictable (page 308, paragraph 3).
The teachings of McArthur demonstrate that new infectious diseases are constantly emerging and that the diseases are unpredictable. These teachings demonstrate that there was no known method to predict infectious disease suggesting that identifying subjects or individuals who would develop an infectious disease was also unpredictable. As such, there was no known method that could be used to predictably identify subjects or individuals for whom infectious disease was prevented using the claimed methods.
Galbadage et al. (in PTO-892) discloses that COVID-19, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has propagated differently among select nations. Galbadage et al. discloses that this raises questions on whether a full scientific understanding of disease transmission modes has yet to be attained, and thus whether there are more effective ways to prevent its spread (see page 1, first and second paragraph). Galbadage et al. discloses there are no current cures or vaccines for SARS-CoV-2 (see page 3 right column), and further illustrates in Figure 1 (page 2) the different potential modes of transmission of COVID-19.
The teachings of Galbadage demonstrate that complete prevention of SARS-CoV-2 is not predictable due to an incomplete understanding in how this condition spreads and thus difficulties to develop more effective methods to prevent transmission. Furthermore, Galbadage discloses several different modes of transmission, which suggests no predictable method to determine how a patient would develop SARS-CoV-2.
Verwij (in PTO-892) discloses that while preventative medicine appears desirable, there are on the other hand ethical problems introduced for administering a treatment to a health patient for the prevention of hypothetical diseases as opposed to the treatment of a patient who is already sick (page 25 second-fourth paragraphs). Verwij discloses that even minor adverse effects could be ethically problematic for patients who are treated in the absence of an actual disease (page 36 section 3.4.1).
The teachings of Verwij establishes that while there may be some hypothetical protective effect of administering a preventative therapy against a disease or condition, such a preventative therapy may not be ethically justified or practically feasible.
Therefore, these teachings demonstrate that there is no method available to predictably determine that a disease would have developed in order to establish that it was prevented.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of a predictable method to identify patients who would develop a disease without treatment, one of ordinary skilled in the art would not be able to predictably identify that a disease was prevented using the claimed agents. Furthermore, the quantity of experimentation would be undue because a method to identify a patient who would predictably get a disease in order to establish that the claimed method results in prevention does not exist.
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 § 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.
Claim(s) 1-5, 9-13, and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over US20190083520A1 (in PTO-892) in view of Kwon et al. (US20170173065A1 in PTO-892) and as evidenced by Secades (Rev Neurol, 2011 in PTO-892).
US’520 discloses N4-hydroxycytidine nucleoside derivatives, as well as compositions and methods to treat viral infections using the compounds thereof (paragraph 0002).
US’520 provides exemplary compounds in FIG. 2 including EIDD-2061 shown below:
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US’520 discloses that their compounds can be used to treat a subject having a viral infection such as zika virus, influenzas, human coronavirus, MERS-CoV, hepatitis A/B/C/D/E, and other viruses (paragraph 0305).
US’520 discloses that their compounds can be formulated into pharmaceutical compositions comprising a pharmaceutically acceptable excipient (paragraph 0308). US’520 discloses their compounds can be in various pharmaceutical forms including tablets, capsules, and others (paragraph 0317). US’520 discloses that their pharmaceutical compositions comprising their compounds can be administered in combination with another antiviral agents including peginterferon alfa-2a and others ( paragraph 0352), which meets the limitation of a standard antiviral therapy as disclosed in lines 4-10 page 13 in the instant specification.
US’520 discloses that their N4-hydroxycytidine compounds can be synthesized in one step by adding hydroxylamine to cytidine (paragraph 0357) as seen in FIG. 1 to hydroxylate the N4 position of the nucleobase. US’520 further demonstrates this hydroxylamine addition using a cytidine triphosphate in Example 9 to form the EIDD-2061 compound (Example 9 paragraphs 0382-0384).
While US’520 discloses several N4-hydroxycytidine compounds derived from a cytidine compound that are useful for treating viral infections such as hepatitis, MERS-CoV, and others, US’520 does not disclose a N4-hydroxycytidine compound that contains the diphosphate-choline moiety as seen in the instant Formula (l) compound. Furthermore, US’520 does not disclose that the instant Formula (l) compound is made using citicoline as recited in instant claim 11.
Kwon teaches antiviral compositions comprising compounds involved in the phosphatidylcholine synthesis pathway such as chlorine, phosphocholine, cytidine triphosphate, CDP-choline, phosphorylcholine, and phosphatidylcholine (Abstract).
The CDP-choline compound disclosed in Kwon is also known as citicoline or cytidine 5’-diphosphocholine as evidenced in lines 8-9 page 1 in the instant specification and has the following structure as evidenced by Secades (Figure 1 page 2) shown below:
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The CDP-choline compound is identical to the instant Formula (l) structure except that the N4 position on the nucleobase is not hydroxylated.
Kwon teaches that their compositions that comprise compounds involved in the phosphatidylcholine synthesis pathway were found to be effective in inhibiting the activation of caspase-3 in a virus, inhibiting cell necrosis, and suppressing the release of progeny viruses, thereby confirming that the substances exhibit antiviral abilities (paragraph 0029 and FIG. 2). Kwon teaches that their compositions are useful for treating several viruses such as rhinovirus, enterovirus, cardiovirus, aphthovirus, or hepatovirus (paragraph 0032). Kwon teaches that the hepatovirus may comprise hepatis A virus (paragraph 0037). Kwon also teaches the virus may be a picornavirus that is a positive single-stranded RNA virus (paragraph 0031).
Kwon demonstrates in Table 1 (paragraph 0096) and FIG. 3 that cytidine triphosphate, CDP-choline, and phosphatidylcholine have a superior effect of inhibiting proliferation of rhinovirus type 2 at the concentration of 1 μg/ml or more, compared to that of ribavirin, an antiviral agent used as the control group (paragraph 0097).
It would have been prima facie obvious before the effective filing date of the claimed invention to modify the method of US’520, in which hydroxylamine is combined with cytidine triphosphate, by substituting the cytidine triphosphate with the CDP-choline as disclosed in Kwon to arrive at the instant Formula (l) compound and methods.
One of ordinary skill in the art would have substituted one known element (cytidine triphosphate) for another (CDP-choline) to obtain predictable results and would have a reasonable expectation of success in doing so because US’520 provides guidance to further derivatize via N4-hydroxylation of cytidine compounds such as cytidine triphosphate that are useful for treating the same RNA viral infections such as hepatitis, and Kwon discloses that both cytidine triphosphate and CDP-choline are involved in the phosphatidylcholine synthesis pathway that have the same effective antiviral properties and can also be used to treat the same viral infections such as hepatitis.
Claim(s) 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over US20190083520A1 (in PTO-892) in view of Kwon et al. (US20170173065A1 in PTO-892) and as evidenced by Secades (Rev Neurol, 2011 in PTO-892), as applied to claims 1, 4, and 12 above, and further in view of US20210252033A1 (published 08/19/2021 in PTO-892).
The combined teachings of US’520 and Kwon are as described above and teach the method of instant claims 1, 4, and 12, as evidenced by Secades, as discussed above.
The combined references, however, do not teach treating a disease caused by SARS-CoV-2 and/or COVID-19, and wherein the disease is a moderate to severe case of the disease..
US’033 discloses N4-hydroxycitidine derivative compounds such as the EIDD-2061 (FIG. 2) and further discloses that these compounds are useful for the treatment of COVID-19 (Abstract and paragraph 0015). US’033 discloses that COVID-19 can include severe respiratory disease in humans and appears to also cause neurological disease that includes dizziness, impaired consciousness, acute cerebrovascular disease, epilepsy, hyposmia, hypopsia, and neuralgia (paragraph 0004). The COVID-19 that includes severe respiratory disease is being interpreted as a severe case of COVID-19 (paragraph 0004).
It would have been prima facie obvious before the effective filing date of the claimed invention that the N4-hydroxy CDP-choline derivative compound as disclosed by the combined teachings of US’520 and Kwon described above can also be used to treat a patient with severe respiratory disease from COVID-19 as disclosed in US’033.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because US’033 provides guidance of the same N4-hydroxycitidine derivative compounds such as the EIDD-2061 compound that are useful for treating COVID-19, and US’033 provides further guidance that COVID-19 can include severe respiratory disease in humans.
Claim(s) 6-7 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over US20190083520A1 (in PTO-892) in view of Kwon et al. (US20170173065A1 in PTO-892) and as evidenced by Secades (Rev Neurol, 2011 in PTO-892), as applied to claim 1 above, and further in view of US20210252033A1 (published 08/19/2021 in PTO-892) and Al-Horani et al. (Viruses, 2020 in PTO-892).
The combined teachings of US’520 and Kwon are as described above and teach the method of instant claim 1, as evidenced by Secades, as discussed above.
The combined references also provide guidance of further administering in combination with other antiviral agents such as peginterferon alfa-2a (paragraph 0352), which meets the limitation of a standard antiviral therapy recited in instant claim 16 as described above.
The combined references, however, do not teach further administering a DHODH inhibitor having the recited Formula (II) structure.
The teachings of US’033 are as described above. In particular, US’033 discloses N4-hydroxycitidine derivative compounds such as the EIDD-2061 (FIG. 2) and further discloses that these compounds are useful for the treatment of COVID-19 (Abstract and paragraph 0015).
Al-Horani discloses potential anti-SARS-CoV-2 therapeutics that target the post-entry stages of the viral life cycle (Abstract).
Al-Horani discloses that a potential anti-SARS-CoV-2 therapeutic compound is vidofludmius (IMU-838) as shown in Figure 7 (page 13) and shown below:
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This vidofludimus (IMU-838) compound meets the structure of the instant Formula (II) structure when R1-R2 and R4-R10 are H, R3 is halogen, A is heterocyclopentenyl, and X is OR11 where R11 is C1-4 alkyl.
Al-Horani teaches that IMU-838 selectively inhibits dihydroorotate dehydrogenase (DHODH) and is known to result in diminishing inflammatory biomarkers as well as have a direct antiviral effect (second paragraph section 4.4. page 16). Al-Horani teaches that IMU-838 antiviral activity has been demonstrated in vitro against arenavirus, cytomegalovirus, influenza A virus, HCV, HIV, as well as SARS-CoV-2 (second paragraph section 4.4. page 16). Al-Horani discloses that IMU-838 promoted the anti-SARS-CoV-2 activity at concentrations lower than those that have been considered in previous and ongoing clinical trials (second paragraph section 4.4. page 16).
It would have been prima facie obvious before the effective filing date of the claimed invention that the N4-hydroxy CDP-choline derivative compound as disclosed by the combined teachings of US’520 and Kwon described above can also be used to treat a patient with severe symptoms of respiratory disease from COVID-19 as disclosed in US’033 and to further include the IMU-838 of Al-Horani in the treatment method against COVID-19 to arrive at the claimed invention.
One of ordinary skill in the art would have made the modification of further using the N4-hydroxy CDP-choline derivative compound described above for treating COVID-19 with a reasonable expectation of success because US’033 provides guidance of the same N4-hydroxycitidine derivative compounds such as the EIDD-2061 compound that are useful for treating COVID-19.
One of ordinary skill in the art would have been motivated to further include IMU-838 because Al-Horani teaches that IMU-838 has added effects of diminishing inflammatory biomarkers, and that IMU-838 promoted the anti-SARS-CoV-2 activity at concentrations lower than those that have been considered in previous and ongoing clinical trials.
One of ordinary skill in the art would have a reasonable expectation of success because both the combined teachings of US’520, Kwon, and US’033 described above, and Al-Horani teach therapeutic compounds that are useful for treating the same COVID-19. Furthermore, the combined teachings of US’520, Kwon, and US’033 described above provide guidance of administering N4-hydroxycytidine compounds in combination with other antiviral agents.
Claim(s) 8 is rejected under 35 U.S.C. 103 as being unpatentable over US20190083520A1 (in PTO-892) in view of Kwon et al. (US20170173065A1 in PTO-892), US20210252033A1 (published 08/19/2021 in PTO-892), Al-Horani et al. (Viruses, 2020 in PTO-892), and as evidenced by Secades (Rev Neurol, 2011 in PTO-892), as applied to claims 1 and 6-7 above, and further in view of Byrd et al. (WO2021134045A1 in PTO-892), Pirali et al. (Journal of Medicinal Chemistry, 2019 in PTO-892), and Muehler et al. (European Journal of Drug Metabolism and Pharmacokinetics, published 05/02/2020 in PTO-892).
The combined teachings of US’520, Kwon, US’033, and Al-Horani are as described above and teach the method of instant claims 1 and 6-7, as evidenced by Secades, as discussed above.
Furthermore, the IMU-838 compound as disclosed by the combined references above has the same structure as the first compound in instant claim 8 except for the deuteration (D) of the three hydrogens on the methyl of the methoxy group on the phenyl ring.
Byrd teaches pharmaceutical combinations and methods for treating a clinical condition by administering a DHODH inhibitor in combination with an anti-CD38 therapeutic agent (Abstract).
Byrd teaches that the treated clinical condition can be a variety of conditions including viral infections such as HIV and adenovirus, and others (paragraph 0751).
Byrd discloses that exemplary DHODH inhibitors are vidofludimas (IMU-838) and others (claim 90 and paragraph 0624).
Byrd further teaches that their disclosed compounds can comprise atoms that are substituted with heavier isotopes such as deuterium (2H), which can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances (paragraph 0117).
Pirali discloses the applications of deuterium in medicinal chemistry (Abstract).
Pirali discloses that precision deuteration goes beyond the pure and simple amelioration of the pharmacokinetic parameters of a drug and might provide an opportunity when facing problems in terms of metabolism-mediated toxicity, drug interactions, and low bioactivation (Abstract).
Pirali provides several examples of precise deuteration to improve the pharmacokinetic properties of several different drugs. One example involved the previse deuteration of the three hydrogens on a methyl in a methoxy group on selective ligands for GABA receptor subunits as shown in compound 10 in Figure 4 (page5280) below:
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Pirali discloses that this ligand displays a key soft position susceptible to O-demethylation and when this position was deuterated, the ligand showed a significant increase in half-life, an almost 2-fold increase in maximal brain concentration in rats (second to last paragraph right column page 5278).
Pirali also discloses another example in which dextromethorphan was also deuterated at the methyl in the methoxy group as shown in compound 30 Figure 6 (page 5281) below:
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Pirali discloses that dextromethorphan is combined with quinidine as quinidine acts as booster, reducing the first-pass metabolism of dextromethorphan to its O-demethylated metabolite and increasing the plasma half-life (last paragraph left column through first paragraph right column page 5281). Pirali disclose that the deuterated dextromethorphan (compound 30) has improved half-life and requires a lower dose of quinidine, therefore theoretically sparing patients of some of the unwanted side effects of the quinidine drug (first paragraph right column page 5281).
Muehler discloses the safety, tolerability, and pharmacokinetics of vidofludimus (IMU-838) (Abstract).
Muehler discloses that in hepatocytes, a total of eight metabolites were identified across different species, and that the main metabolite formed in humans was from O-demethylation (first paragraph left column page 558).
It would have been prima facie obvious before the effective filing date of the claimed invention to further modify the IMU-838 compound as disclosed by the combined teachings of US’520, Kwon, US’033, and Al-Horani described above by deuterating the methyl on the methyoxy group of the compound as suggested by Byrd, Pirali, and Muehler to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to deuterate the IMU-838 compound at the methyl on the methoxy group because both Byrd and Pirali disclose that deuteration of compounds can provide certain therapeutic advantages resulting from greater metabolic stability such as increased in vivo half-life or reduced dosage requirements.
One of ordinary skill in the art would have a reasonable expectation of success because Byrd provides guidance of deuterating their compounds which includes the IMU-838 compound. Furthermore, an ordinary skilled artisan would have been able to determine through routine experimentation to deuterate the methyl on the methoxy group on the IMU-838 compound with a reasonable expectation of success because Pirali provides guidance of precisely deuterating the methyl on the methoxy groups of therapeutic compounds to protect it from O-demethylation metabolite formation, and Muehler provides further guidance that the main metabolite formed in humans for the IMU-838 compound was from O-demethylation.
It is noted that the instant specification was examined for a showing of unexpected results for the combined administration of the Formula (I) compound and the recited DHODH inhibitor compounds in instant claim 8.
Applicant has demonstrated a synergistic effect in Examples 101-103 when administering the Formula (l) compound with the first DHODH inhibitor compound in instant claim 8 against SARS-CoV-2, HRV-14, influenza A, and RSV.
Applicant demonstrates in FIG. 1 that the combination at 1x to 4x EC50 dosages produced a synergistic viral inhibition effect in a SARS-CoV-2 inhibition assay.
Applicant further demonstrates in the second table on page 26 that a combination of 25 micromolar of the Example 50 compound (first DHODH compound in instant claim 8) with 0.0079 to 25 micromolar of the Example 1 compound (the instant Formula (l) compound) resulted in antiviral synergy against RSV. Applicant also appears to demonstrate in the third table on page 26 the same synergy effect against HRV-14 virus.
As stated in MPEP 716.02(e), the showing of an unexpected result must be compared with the closet prior art to be effective to rebut a prima facie case of obviousness.
In this case, the closest prior arts are US’033, which discloses N4-hydroxycytidine derivative compounds for use against COVID-19, and Byrd, which discloses the IMU-838 DHODH inhibitor compound for use against COVID-19.
Applicant does appear to demonstrate a showing of unexpected results over the closest prior arts because as described above, Applicant has demonstrated a synergistic effect when combining these two types of compounds together, and the combined use of these two types of compounds (N4-hydroxycytidine derivative compounds and DHODH inhibitors) is not known or suggested in the prior art.
However, MPEP 716.02(d) states that the showing of unexpected results must be commensurate in scope with the claim invention.
Currently, claim 1 recites a method of treating any disease by administering any amount of just the Formula (l) compound, and Applicant has only demonstrated the synergistic effect in certain amounts of the Formula (l) compound and a specific DHODH inhibitor (first compound in instant claim 8).
Additionally, Applicant has only demonstrated a synergistic effect against SARS-CoV-2, HRV-14, influenza A, and RSV, and not toward any disease as well as several of the other recited conditions in instant claims 4 and 12 such as AIDS, hepatitis, ebola, diarrhea, etc.
While MPEP 716.02(d) I states that nonobviousness of a broader claimed range can be supported by evidence based on unexpected results, it cannot be determined by the exemplified data any trend which would allow any ordinary skilled artisan to reasonably determine that the use of any amount of the Formula (l) compound and any DHODH inhibitor compound against any of the recited diseases would also have the exemplified synergistic effect.
Therefore, Applicant’s currently recited claims and showing of unexpected results in the instant specification is not enough to establish nonobviousness over the current rejections.
Conclusion
No claim is found allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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