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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/03/2026 has been entered.
The amendment filed 06/03/2026, amended claims 1, 12, 15 and 18, and cancelled claims 8 and 13.
Claims 1, 4-7, 9-12, and 14-18 are pending.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant elected Group I, the method of use, in the reply filed 08/08/2025.
Claims 12, 14 and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 4-7, 9-11, 15-16, and 18 are examined on the merits herein.
REJECTIONS—MODIFIED & MAINTAINED
Though the rejections are modified, the same primary reference continues to be relied upon in the prior art rejection. Since WO 2013/157005 and US 9,616,067 are in the same patent family, the prior art rejections are simplified to a single rejection over WO 2013/157005, instead of a rejection over WO 2013/157005 and another rejection over US 9,616,067.
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.
(Maintained) Claim 5 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.
-The term “standard” in relation to the daily dose of artemisone and letermovir or brincidofovir, in claim 5, is a relative term which renders the claim indefinite. The phrase “standard daily dose” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, i.e., a standard daily dose, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
While paragraph [0052] of the specification states “The suggested oral dose of artemisone is from 80 to 500 mg/day. . .the dose of artemisone in the combination is from 80-250 mg/day. . .the IV dose of artemisone in the combination is from 0.2 to 2. . .mg/kg/day,” these amounts appear to be examples of therapeutically effective amounts to treat viral infection, and not a “standard daily dose” of artemisone, letermovir, and brincidofovir.
Moreover, the prior art does not teach standard dosage amounts of either artemisone, letermovir, or brincidofovir alone or in combination. As pointed out by Applicant on pg. 6, Remarks, the FDA does teach a standard dosage amount of letermovir and brincidofovir. However, the FDA prescribing information states that the dosage amount of letermovir is for use in “prophylaxis of cytomegalovirus” and not treatment of a cytomegalovirus infection, and the FDA prescribing information states that the dosage amount of brincidofovir, is “is not indicated for the treatment of diseases other than human smallpox disease,” i.e., it is only for the treatment of human smallpox disease.
See MPEP2173.05(b)(ii), a claim may be rendered indefinite when a limitation of the claim is defined by reference to an object and the relationship between the limitation and the object is not sufficiently defined. That is, where the elements of a claim have two or more plausible constructions such that the examiner cannot readily ascertain positional relationship of the elements, the claim may be rendered indefinite.
In view of compact prosecution, for the purpose of applying prior art, “the daily administered dose of artemisone and/or of said compound is lower than the standard daily dose of artemisone and/or of said compound,” is interpreted as any amount known to treat a viral infection.
Response to 112(b) Arguments
On pg. 5, Remarks, Applicant argues that “standard daily dose” is a term well known and understood in the art and Applicant points to US Patent No. 8492441.
This argument has been fully considered, but is not found persuasive. ‘441 is directed toward distinct compounds, and it is unknown if S1P receptor agonists were well known in the art to be administered at specific dosage amounts. Moreover, a single patent published over 10 years ago is not evidence that the term is “well known and understood in the art,” especially in reference to the specific compounds artemisone, letermovir, and brincidofovir in their treatment of beta herpesviruses.
On pg. 6, Remarks, Applicant argues that letermovir and brincidofovir are FDA approved drugs for treating viral disease and then recites the prescribing information for these drugs on the FDA website.
This argument has been fully considered, but is not found persuasive. It is first respectfully pointed out that Applicant has not pointed to evidence that “a standard daily dose” of artemisone, in general or in reference to treating beta herpesvirus, is known in the art. Regarding the FDA prescribing information, it is respectfully pointed out that the prescribing information for letermovir states its use for “prophylaxis of cytomegalovirus” and that the prescribing information for brincidofovir states that it “is not indicated for the treatment of diseases other than human smallpox disease.” As such, the FDA prescribing information does not provide evidence that a standard daily dose of artemisone, letermovir, or brincidofovir, for the treatment of beta herpesviruses is well known and understood in the art.
On pg. 6, Remarks, Applicant argues that Haynes teaches that “The amount of a compound of the invention that will be effective in the treatment of a particular disorder or condition, including human cytomegalovirus (HCMV), will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques,” and that this statement provides evidence of a “standard daily dose.”
This argument has been fully considered, but is not found persuasive. It is respectfully pointed out that Hayes is referencing a “therapeutically effective amount” of a compound and not a “standard daily dose.” See Col. 23, lines 35-Col. 24, line 6 of US 9616067 to Haynes.
Moreover, regarding “an effective amount,” MPEP 2173.05(c)(III) states, “The common phrase "an effective amount" may or may not be indefinite. The proper test is whether or not one skilled in the art could determine specific values for the amount based on the disclosure. See In re Mattison, 509 F.2d 563, 184 USPQ 484 (CCPA 1975). The phrase "an effective amount . . . for growth stimulation" was held to be definite where the amount was not critical and those skilled in the art would be able to determine from the written disclosure, including the examples, what an effective amount is. In re Halleck, 422 F.2d 911, 164 USPQ 647 (CCPA 1970). The phrase "an effective amount" has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In re Fredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). The more recent cases have tended to accept a limitation such as "an effective amount" as being definite when read in light of the supporting disclosure and in the absence of any prior art which would give rise to uncertainty about the scope of the claim. In Ex parte Skuballa, 12 USPQ2d 1570 (Bd. Pat. App. & Inter. 1989), the Board held that a pharmaceutical composition claim which recited an "effective amount of a compound of claim 1" without stating the function to be achieved was definite, particularly when read in light of the supporting disclosure which provided guidelines as to the intended utilities and how the uses could be effected.”
In the instant case, the instant specification has not correlated an effective amount of artemisone or letermovir or brincidofovir to treat beta herpesvirus, with a “standard daily dose” of any of these compounds.
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 1, 4-7, 9-11, 15-16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2013/157005 to Haynes (published 2013, IDS of 01/20/2023) in view of Wildum (In Vitro Drug Combination Studies of Letermovir with Approved Anti-uman Cytomegalovirus and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication, published 2015, PTO-892) and Koizumi (Mathematical modeling of multi-drugs therapy: a challenge for determining the optimal combinations of antiviral drugs, published 2014, PTO-892), as evidenced by PubChem (Brincidofovir, PTO-892 of 10/07/2025).
Haynes teaches a method of treating a herpesvirus infection or suppressing herpesvirus replication or a method of treating human cytomegalovirus, comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of artemisone (pgs. 58-61, claims 30, 34, 38-40).
Haynes additionally teaches co-administering an anti-viral drug (pgs. 61-62, claims 44-45).
Haynes exemplifies a method of treating HCMV by administering a combination of artemisone and ganciclovir (pg. 40, example 5), and Haynes further teaches that artemisone demonstrates a novel mechanism of action, different from that of ganciclovir, which involves inhibition of a very early step of viral replication preceding viral DNA synthesis (pg. 39, lines 3-9).
Regarding claims 1, 9-10, 15-16, and 18, while Haynes teaches a method of treating cytomegalovirus by administering artemisone and ganciclovir, the anti-viral, it differs from that of claims 1, 9-10, 15-16, and 18 in that it does not teach letermovir or brincidofovir as the anti-viral.
Haynes further teaches combination therapy of its compound in combination with a viral DNA polymerase inhibitor, such as ganciclovir, letermovir or brincidofovir (CMX-001), and teaches that each possibility represents a separate embodiment of the invention (pg. 30, lines 3-18).
As evidenced by PubChem (Brincidofovir), CMX-001 is brincidofovir.
Wildum teaches that all drugs currently licensed for the treatment of HCMV infection target the viral polymerase and are associated with severe toxicity issues and the emergence of drug resistance. Wildum teaches letermovir as a new anti-HCMV agent in clinical development that acts via a novel mode of action and has demonstrated anti-HCMV activity, and that in drug combination therapies, letermovir is useful in transplant patients with multidrug-resistant virus strains or in HCMV-HIV coinfected patients. Wildum teaches that mathematical techniques are used to analyze the additive effects observed for the combination of letermovir with other anti-HCMV drugs (abstract; pg. 3147, last paragraph).
Wildum teaches letermovir, in contrast to all the anti-HCMV drugs marketed, targets the pUL56 subunit of the viral terminase complex and thus interferes with viral DNA maturation and packaging. Owing to the absence of a human counterpart for the viral terminase enzyme, the drug has the advantage of reducing toxicity (pg. 3141, 1st full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the ganciclovir with letermovir in the methods of Haynes, to arrive at instant claims 1, 9-10, and 15-16. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Haynes teaches co-administering an anti-viral drug with artemisone for the treatment of herpesvirus or human cytomegalovirus, and exemplifies a method of treating HCMV with artemisone and the anti-viral ganciclovir,
-Haynes teaches letermovir or ganciclovir as viral DNA polymerase inhibitors for use as its anti-viral drugs,
- Wildum teaches letermovir as a new anti-HCMV agent in clinical development that acts via a novel mode of action, and that in drug combination therapies letermovir is useful in transplant patients with multidrug-resistant virus strains or in HCMV-HIV coinfected patients,
-Wildum teaches letermovir as having reduced toxicity in comparison to other known HCMV drugs and Wildum teaches ganciclovir as a known HCMV drug (pg. 3140, Col. 2; pg. 3145, Table 3).
As such, an ordinary skilled artisan would have been motivated to make such a substitution, to predictably arrive at a method of treating HCMV that is less toxic and more effective in the treatment of transplant patients with multidrug-resistant virus strains and in patients co-infected with HCMV and HIV.
Further regarding claims 1 and 15, the combination of Haynes and Wildum does not teach the molar ratios of artemisone to letermovir or artemisone to brincidofovir.
Haynes teaches “a therapeutically effective amount” refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject. In one amount, the therapeutic benefit is inhibiting virus activity. Haynes further teaches that the administration regiment can be determined by a skilled artisan depending on the infection and the severity of the condition, the patient population, age, weight, etc. The amount of a compound of the invention that will be effective in the treatment of a particular disorder or condition, including HCMV, will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro assays, animal assays and the ex-vivo assay described herein below, may optionally be employed to help identify optimal dosage ranges. The precise range to be employed also depends on the route of administration, and the progression of the disease or disorder, and should be decided according to the judgement of the practitioner and each patient’s circumstances. Haynes teaches specific mg/kg amounts and further teaches that the amount administered can be measured and expressed as molarity of the administered compound, wherein artemisone can be administered in a range of 0.1uM to 10mM. By way of illustration and not limitation, an antiviral agent can be administered in an amount of 1 ng/ml to 1000mg/ml, for example, wherein effective doses may be extrapolated from dose-response curves derived from an in-vitro animal model or ex-vivo model test bioassays or systems (pg. 34, lines 1-26).
Koizumi teaches that in the current era of antiviral drug therapy, combining multiple drugs is a primary approach for improving antiviral effects, reducing the doses of individual drugs, relieving the side effects of strong antiviral drugs, and preventing the emergence of drug-resistant viruses. Koizumi teaches that mathematical models of viral infection dynamics provide an ideal tool, and that such models can assess drug combination synergism by two prominent drug combination theories, Loewe additivity and Bliss independence. “By combining the mathematical modeling of virus dynamics with drug combination theories, we could show the principles by which drug combinations yield a synergistic effect” (Abstract).
Koizumi teaches that Loewe additivity is determined by the concentration ratio of a single drug and its combination with another drugs (pgs. 2-3, “Basic drug combination theory: Loewe additivity”). Koizumi teaches that this technique predicts the optimal drug combination that both reduces the total dose of each drug and enhances the antiviral effects (pg. 4).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the molar amounts of artemisone to letermovir, in the combined method of Haynes and Wildum, to arrive at instant claims 1 and 15, and hence the synergistic antiviral effect. One of ordinary skill in the art would have been motivated to make such modifications, with a reasonable expectation of success, because:
- Haynes teaches that “a therapeutically effective amount” refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject,
-Haynes teaches that the amount of a compound of the invention that will be effective in the treatment of a particular disorder or condition, including HCMV, will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques,
-Haynes teaches that the amount administered can be measured and expressed as molarity of the administered compound, wherein artemisone can be administered in a range of 0.1uM to 10mM,
-Haynes teaches that an antiviral agent can be administered in an amount of 1 ng/ml to 1000mg/ml, for example, wherein effective doses may be extrapolated from dose-response curves derived from an in-vitro animal model or ex-vivo model test bioassays or systems,
-Koizumi teaches that mathematical models in combination with prominent drug combination theories, such as Loewe additivity and Bliss independent, of viral infection are a tool known in the art to evaluate drug combinations for additive and synergistic effect,
-Koizumi teaches Loewe additivity as determined by concentration ratios of the drugs, and
- "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." MPEP 2144.05(II).
As such, an ordinary skilled artisan would have been motivated to make such modifications to predictably arrive at the most therapeutically effective molar combination of artemisone to letermovir that is effective to treat human cytomegalovirus.
Additionally, regarding claims 1 and 15, in view of the above obviousness rationales, since the combination of Haynes, Wildum, and Koizumi teaches a method of treating the same viral infection in the same patient population in the same molar ratios, the method would be expected to provide a synergistic antiviral effect.
Further regarding the wherein clauses in claims 1 and 15, per MPEP 2111.04, “ (a) ‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). In the instant case, the wherein clauses express the desired result of the positive step of administering a combination of artemisone and letermovir, in specific molar ratios, to patients with herpesvirus or cytomegalovirus. Since the combination of Haynes, Wildum, and Koizumi teaches such a method, this limitation is met.
Regarding claims 4 and 6, Haynes teaches the co-administering as a single combined composition, separate individual compositions administered substantially at the same time, or separate individual compositions administered under separate schedules (pg. 62, claim 46; pg. 11, line 30-pg. 12, line 5).
Regarding claim 5, since Haynes teaches amounts of artemisone and letermovir effective to treat viral infections, the limitations of this claim are met. See the interpretation of this claim in the 112(b) section above. The optimization of known amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
Regarding claim 7, Haynes teaches its pharmaceutical composition as further comprising a pharmaceutically acceptable carrier or excipient (pg. 61, claim 41).
Regarding claims 9 and 18, Haynes teaches HCMV.
Regarding claims 10 and 16, Haynes teaches its methods as suppressing herpesvirus replication.
Regarding claim 11, Haynes teach its methods for the treatment of newborns, pregnant women, and transplant recipients (pg. 6, lines 14-28; pg. 29, line 24-pg. 30, line 2). M
Response to Prior Art Arguments
The prior art rejections have been modified. As such, only arguments pertinent to the above rejection will be addressed.
Regarding Applicant’s arguments directed toward unexpected results, it is respectfully pointed out that that neither Example 1 nor Tables 4-5 are commensurate in scope with the instant independent claims 1 and 15. Both claims 1 and 15 are directed toward a method of treating any beta herpesvirus, while the instant examples are specifically directed toward a single beta herpesvirus, HCMV, and a single molar ratio of artemisone to letermovir (200:1) and a single ratio of artemisone to brincidofovir (1000:1). MPEP 716.02 states that unexpected results must be commensurate in scope with the claimed invention and provide a comparison with the closest prior art, and MPEP 716.02(d) specifically states “To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range.”
As such, Applicant’s arguments of unexpected results are not persuasive to overcome the instant rejections.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 4-7, 9-11, 15-16, and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 9,616,067 in view of WO 2013/157005 to Haynes (published 2013, IDS of 01/20/2023), Wildum (In Vitro Drug Combination Studies of Letermovir with Approved Anti-uman Cytomegalovirus and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication, published 2015, PTO-892) and Koizumi (Mathematical modeling of multi-drugs therapy: a challenge for determining the optimal combinations of antiviral drugs, published 2014, PTO-892), as evidenced by PubChem (Brincidofovir, PTO-892 of 10/07/2025),
‘067 claims a method of treating herpesvirus and cytomegalovirus, or a method of suppressing herpesvirus or cytomegalovirus replication, by administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and artemisone and an anti-viral, such as ganciclovir (claims 1, 3, 6-7, 9, 11, 14-15).
‘067 differs from that of instant claims 1 and 15 in that it does not teach letermovir as the anti-viral or the instantly claimed molar ratios.
Haynes, Wildum, and Koizumi are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the ganciclovir with letermovir in the methods of Haynes, to arrive at instant claims 1, 9-10, and 15-16. One of ordinary skill in the art would have been motivated to make such selections, with a reasonable expectation of success, because:
-‘067 and Haynes teaches co-administering an anti-viral drug with artemisone for the treatment of herpesvirus or cytomegalovirus, and Haynes exemplifies a method of treating HCMV with artemisone and the anti-viral ganciclovir,
-Haynes teaches letermovir or ganciclovir as viral DNA polymerase inhibitors for use as its anti-viral drugs,
-Wildum teaches letermovir as a new anti-HCMV agent in clinical development that acts via a novel mode of action, and that in drug combination therapies, letermovir is useful in transplant patients with multidrug-resistant virus strains or in HCMV-HIV coinfected patients,
-Wildum teaches letermovir as having reduced toxicity in comparison to other known HCMV drugs and Wildum teaches ganciclovir as a known HCMV drug (pg. 3140, Col. 2; pg. 3145, Table 3).
As such, an ordinary skilled artisan would have been motivated to make such a substitution, to predictably arrive at methods of treating HCMV that is less toxic and more effective in transplant patients with multidrug-resistant virus strains and in patients co-infected with HCMV and HIV.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the molar amounts of artemisone to letermovir, in the combined method of ‘067, Haynes and Wildum, to arrive at instant claims 1 and 15. One of ordinary skill in the art would have been motivated to make such modifications, with a reasonable expectation of success, because:
- Haynes teaches that “a therapeutically effective amount” refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject,
-Haynes teaches that the amount of a compound of the invention that will be effective in the treatment of a particular disorder or condition, including HCMV, will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques,
-Haynes teaches that the amount administered can be measured and expressed as molarity of the administered compound, wherein artemisone can be administered in a range of 0.1uM to 10mM,
-Haynes teaches that an antiviral agent can be administered in an amount of 1 ng/ml to 1000mg/ml, for example, wherein effective doses may be extrapolated from dose-response curves derived from an in-vitro animal model or ex-vivo model test bioassays or systems,
-Koizumi teaches that mathematical models in combination with prominent drug combination theories, such as Loewe additivity and Bliss independent, of viral infection are a tool known in the art to evaluate drug combinations for additive and synergistic effect,
-Koizumi teaches Loewe additivity as determined by concentration ratios of the drugs, and
- "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." MPEP 2144.05(II).
As such, an ordinary skilled artisan would have been motivated to make such modifications to predictably arrive at the most therapeutically effective synergistic molar combination of artemisone to letermovir to treat human cytomegalovirus.
Additionally, regarding claims 1 and 15, in view of the above obviousness rationales, since Haynes teaches a method of treating the same viral infection in the same patient population in the same molar ratios, the “synergistic” limitations are met. See MPEP 2112.02.
Regarding the wherein clauses in claims 1 and 15, per MPEP 2111.04, “ (a) ‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). In the instant case, the wherein clauses express the desired result of the positive step of administering a combination of artemisone and letermovir or brincidofovir, in specific molar ratios, to patients with herpesvirus or cytomegalovirus. Since the combination of ‘067, Haynes, Wildum, and Koizumi teach a method of treating HCMV by administering artemisone and letermovir in the instantly claimed ratio, this limitation is met.
Regarding claims 4 and 6, ‘067 claims the co-administering as a single combined composition, separate individual compositions administered substantially at the same time, and separate individual compositions administered under separate schedules (Col. 34, claim 8; Col. 36, claim 16).
Regarding claim 7, ‘067 claims a composition comprising artemisone, an anti-viral, and a pharmaceutically acceptable carrier or excipient (claims 1, 9).
See the above prior art rejection to see how the additional claim limitations are met.
Claims 1, 4-7, 9-11, 15-16, and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 10,111,884 (published 2018, IDS of 01/20/2023) in view of WO 2013/157005 to Haynes (published 2013, IDS of 01/20/2023), Wildum (In Vitro Drug Combination Studies of Letermovir with Approved Anti-uman Cytomegalovirus and Anti-HIV Compounds in Inhibition of HCMV and HIV Replication, published 2015, PTO-892) and Koizumi (Mathematical modeling of multi-drugs therapy: a challenge for determining the optimal combinations of antiviral drugs, published 2014, PTO-892) as evidenced by PubChem (Brincidofovir, PTO-892 of 10/07/2025),
‘884 claims a method of treating human cytomegalovirus or suppressing cytomegalovirus replication by administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and artemisone and an antiviral, such as ganciclovir (claims 1, 6-7, 9, 11, 18, 21, 23).
‘884 differs from that of instant claims 1 and 15 in that it does not teach letermovir as the anti-viral or the instantly claimed molar ratios.
Haynes, Wildum, and Koizumi are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the ganciclovir with letermovir in the methods of Haynes, to arrive at instant claims 1, 9-10, and 15-16. One of ordinary skill in the art would have been motivated to make such selections, with a reasonable expectation of success, because:
-‘884 and Haynes teaches co-administering an anti-viral drug with artemisone for the treatment of herpesvirus or cytomegalovirus, and Haynes exemplifies a method of treating HCMV with artemisone and the anti-viral ganciclovir,
-Haynes teaches letermovir or ganciclovir as viral DNA polymerase inhibitors for use as its anti-viral drugs,
-Wildum teaches letermovir as a new anti-HCMV agent in clinical development that acts via a novel mode of action, and that in drug combination therapies, letermovir is useful in transplant patients with multidrug-resistant virus strains or in HCMV-HIV coinfected patients,
-Wildum teaches letermovir as having reduced toxicity in comparison to other known HCMV drugs and Wildum teaches ganciclovir as a known HCMV drug (pg. 3140, Col. 2; pg. 3145, Table 3).
As such, an ordinary skilled artisan would have been motivated to make such a substitution, to predictably arrive at methods of treating HCMV that is less toxic and more effective in transplant patients with multidrug-resistant virus strains and in patients co-infected with HCMV and HIV.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the molar amounts of artemisone to letermovir, in the combined method of ‘884, Haynes and Wildum, to arrive at instant claims 1 and 15. One of ordinary skill in the art would have been motivated to make such modifications, with a reasonable expectation of success, because:
- Haynes teaches that “a therapeutically effective amount” refers to an amount of an agent which is effective, upon single or multiple dose administration to the subject in providing a therapeutic benefit to the subject,
-Haynes teaches that the amount of a compound of the invention that will be effective in the treatment of a particular disorder or condition, including HCMV, will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques,
-Haynes teaches that the amount administered can be measured and expressed as molarity of the administered compound, wherein artemisone can be administered in a range of 0.1uM to 10mM,
-Haynes teaches that an antiviral agent can be administered in an amount of 1 ng/ml to 1000mg/ml, for example, wherein effective doses may be extrapolated from dose-response curves derived from an in-vitro animal model or ex-vivo model test bioassays or systems,
-Koizumi teaches that mathematical models in combination with prominent drug combination theories, such as Loewe additivity and Bliss independent, of viral infection are a tool known in the art to evaluate drug combinations for additive and synergistic effect,
-Koizumi teaches Loewe additivity as determined by concentration ratios of the drugs, and
- "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." MPEP 2144.05(II).
As such, an ordinary skilled artisan would have been motivated to make such modifications to predictably arrive at the most therapeutically effective synergistic molar combination of artemisone to letermovir to treat human cytomegalovirus.
Regarding claims 4 and 6, ‘884 claims the co-administering as a single combined composition, separate individual compositions administered substantially at the same time, and separate individual compositions administered under separate schedules (claims 8, 15).
Regarding claim 7, ‘884 claims a pharmaceutically acceptable carrier (claims 1, 9, 18, 21).
Regarding claims 10 and 16, ‘884 claims suppressing viral replication (claims 1, 9)
Regarding claim 11, ‘884 claims administration to a newborn, pregnant woman, and transplant recipient (claim 17).
Note: A Double Patenting rejection is not made over US 11,583,537, since the instant application is a divisional of 17/026,593, wherein the Examiner in ‘593 did not extend the search beyond an elected combination of artemisone and maribavir, wherein letermovir and brincidofovir were deleted from the claims when the elected combination was allowed.
See the above prior art rejection to see how the additional claim limitations are met.
Response to Arguments
On pg. 15, Remarks, Applicant requests that these rejections be held in abeyance.
This request is acknowledged.
Conclusion
No claims are allowed.
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/LAUREN WELLS/Examiner, Art Unit 1622
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