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
This Office Action is in response to Applicant’s Arguments and Amendment filed, 12/19/2025, wherein the Amendment amended claims 1, 7, and 15, cancelled claims 2-3, and added claim 18.
Claims 1 and 4-18 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Claims 12-14 and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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, 4-11, 15-16, and 18 are examined on the merits herein.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
35 U.S.C. § 112(b)
-Applicant’s amendment to claim 7 is sufficient to overcome the rejection of this claim.
-Applicant’s addition of the molar ratios in claim 15 is sufficient to overcome the rejection of this claim. See also [0009] of the Specification which states that these molar ratios provide a synergistic effect.
REJECTIONS—MAINTAINED & MODIFIED
Applicant’s amendments to independent claims 1 and 15, and addition of claim 18, have resulted in the below slightly modified prior art rejections. The same primary references continue to be relied upon as primary references.
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 the therapeutically effective amounts to treat viral infection, and not the “standard daily dose” of artemisone, letermovir, and brincidofovir.
Moreover, since artemisone, letermovir, and brincidofovir are known in the art to treat different diseases/disorders, it is further unclear what baseline is being referenced from which a “standard daily dose” can be extrapolated.
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
Regarding the rejection over claim 5, on pg. 6, Remarks, Applicant argues a) that “standard daily dose” is a term well known and understood in the art; b) that the doses that should be administered are provided by FDA or other relevant official parties, and c) that it would be clear to an ordinary skilled artisan what would be considered a dose that is lower than the standard one.
These arguments have been fully considered, but are not found persuasive. Applicant is respectfully reminded that the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), MPEP 716.01(c). In the instant case, Applicant has provided no evidence that a “standard daily dose” in reference to artemisone, letermovir, and brincidofovir, is well known and understood in the art.
As discussed above, “standard daily dose” in reference to artemisone, letermovir, and brincidofovir, is a relative term that is neither definitively defined by the instant specification nor by the prior art.
Moreover, a search of patents in PE2E (the patent database) of “standard” near2 (dose or dosage), in combination with the instant classification, yielded 12 results with the term “standard dose” or “standard dosage” in the claims. Of these 12 results, 4 of the results additionally defined the “standard dose” in the claims, and 2 additional results defined “standard dose” in the specification.
As such, the term “standard daily dose” is not a term well known and understood in the art, as argued by Applicant.
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 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.
(Slightly Modified) Claims 1, 4-11, 15-16, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over US 9,616,067 to Haynes (published 2017, IDS of 01/20/2023), as evidenced by PubChem (Brincidofovir, PTO-892).
Haynes teaches a method of treating a herpesvirus infection or suppressing herpesvirus replication or a method of treating a cytomegalovirus having oncomodulatory activity on the development of glioblastoma, comprising administering to a subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a therapeutically effective amount of artemisone (Cols. 33-34, claims 1, 3, 9, 11).
Haynes additionally teaches co-administering an anti-viral drug (Col. 34, claims 6-8; Col. 36, claims 14-15).
Regarding claims 1, 10 and 15-16, while Haynes teaches a method of treating herpesvirus, and specifically cytomegalovirus, by administering artemisone and an anti-viral, it differs from that of claims 1 and 15 in that it does not teach letermovir or brincidofovir as the antiviral.
Haynes teaches ganciclovir, foscarnet, cidofovir, valganciclovir, foscarnet, acyclovir, valacyclovir, maribavir, letermovir and brincidofovir (CMX-001) as anti-virals for use in its methods (Co. 20, line 63-Col. 21, line 18).
As evidenced by PubChem (Brincidofovir), CMX-001 is brincidofovir.
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 select letermovir or brincidofovir as the antiviral in the methods of Haynes, to arrive at instant claims 1, 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:
-Haynes teaches co-administering an anti-viral drug with artemisone for the treatment of herpesvirus or cytomegalovirus, and
-Haynes teaches letermovir and brincidofovir as such anti-viral drugs.
As such, an ordinary skilled artisan would have been motivated to make such selections, to predictably arrive at methods of treating herpesvirus and cytomegalovirus that are therapeutically effective and optimized for anti-viral effect.
Further regarding claims 1 and 15, while Haynes teaches a method of treating herpesvirus, and specifically cytomegalovirus, by administering artemisone and letermovir or brincidofovir, it differs from that of claim 1 and 15 in that it does not teach the molar ratios of artemisone to letermovir or artemisone to brincidofovir.
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. In one amount, the therapeutic benefit is inhibiting virus activity (Col. 13-Col. 14, line 6). Haynes further teaches that the administration regimen 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 human cytomegalovirus (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 models or ex-vivo model test bioassays or systems (Col. 23, line 35-Col. 24, line 6).
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 and artemisone to brincidofovir, 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 “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, 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 combination of artemisone and letermovir or brincidofovir, to treat herpesvirus or 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.
Regarding claims 4 and 6, Haynes teaches the co-administering of the anti-viral with artemisone 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 5, since Haynes teaches amounts of artemisone and letermovir or brincidofovir to treat viral infections, the limitations of this claim are met. See the interpretation of this claim in the 112(b) section above.
Regarding claim 7, Haynes teaches a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of artemisone.
Regarding claims 8-9, and 18 Haynes teaches the viral infection as a herpesvirus and specifically teaches a human cytomegalovirus (Col. 3, lines 30-44; Col. 4, lines 47-67; Col. 6, lines 6-14; Col. 19, line 46-Col. 20, line 5; Col. 33-34, claims 1 and 9).
Regarding claim 11, Haynes teach its methods for the treatment of newborns, pregnant women, and transplantation recipients (Col. 20, lines 49-62).
Claims 1, 4-11, 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), as evidenced by PubChem (Brincidofovir, PTO-892).
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).
Regarding claims 1, 8-10, 15-16, and 18, while Haynes teaches a method of treating herpesvirus, and specifically cytomegalovirus, by administering artemisone and an anti-viral, it differs from that of claims 1, 8-10, 15-16, and 18 in that it does not teach letermovir or brincidofovir as the antiviral.
Haynes teaches ganciclovir, foscarnet, cidofovir, valganciclovir, foscarnet, acyclovir, valacyclovir, maribavir, letermovir and brincidofovir (CMX-001) as antivirals for use in its methods (pg. 30, lines 3-18).
As evidenced by PubChem (Brincidofovir), CMX-001 is brincidofovir.
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 select letermovir or brincidofovir as the antiviral in the methods of Haynes, to arrive at instant claims 1, 8-10, 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:
-Haynes teaches co-administering an anti-viral drug with artemisone for the treatment of herpesvirus or human cytomegalovirus, and
-Haynes teaches letermovir and brincidofovir as such anti-viral drugs.
As such, an ordinary skilled artisan would have been motivated to make such selections, to predictably arrive at methods of treating herpesvirus and human cytomegalovirus that are therapeutically effective and optimized for anti-viral effect.
Further regarding claims 1 and 15, while Haynes teaches a method of treating herpesvirus, and specifically cytomegalovirus by administering artemisone and letermovir or brincidofovir, it differs from that of claim 1 and 15 in that it 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).
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 and artemisone to brincidofovir, 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, 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 combination of artemisone and letermovir or brincidofovir, to treat herpesvirus or 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.
Regarding claims 4 and 6, Haynes teaches 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 (pg. 62, claim 46; pg. 11, line 30-pg. 12, line 5).
Regarding claim 5, since Haynes teaches amounts of artemisone and letermovir or brincidofovir to treat viral infections, the limitations of this claim are met. See the interpretation of this claim in the 112(b) section above.
Regarding claim 7, Haynes teaches its pharmaceutical composition as further comprising a pharmaceutically acceptable carrier or excipient (pg. 61, claim 41).
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).
Response to Prior Art Arguments
Note: On pgs. 7, Remarks, Applicant states “Claims 1-11 and 15-16 are rejected under 35 USC 103 as being unpatentable over US 9,616,067 in view of WO 2013/157005 to Haynes,” and on pg. 9, Remarks, Applicant states “Claims 1-11 and 15-16 are rejected under 35 USC 103 as being unpatentable over WO 2013/157005 in view of US 9,616,067 to Haynes,” However, the prior art rejections are not over US 9,616,067 in view of WO 2013/157005 to Haynes, but over US 9,616,067 to Haynes and over WO 2013/157005 to Haynes, individually, i.e., two separate prior art references over two separate primary references.
On pg. 7, Remarks, Applicant argues that Haynes does not teach that the anti-viral drug is letermovir or brincidofovir, but that Haynes teaches ganciclovir, foscarnet, cidofovir, valganciclovir, acyclovir, valacyclovir, maribavir, letermovir and brincidofovir (CMX-001) as antivirals for use in its methods.
This argument has been fully considered but is not found persuasive. This argument is not clear. Applicant states that Haynes does not teach letermovir or brincidofovir as anti-virals, but then goes on to state that Haynes teaches both letermovir and brincidofovir (CMX-001) as anti-virals. While Haynes teaches seven additional anti-virals, Haynes still teaches letermovir and brincidofovir as anti-virals. Thus, Haynes teaches letermovir and brincidofovir.
On pg. 8, Remarks, Applicant argues that Haynes does not teach molar ratios of artemisone to letermovir or brincidofovir.
This argument has been fully considered, but is not found persuasive. While the examiner agrees that the claimed molar ratios are not anticipated by Haynes, the teachings of Haynes render the molar ratios obvious. As discussed in the above rejection,
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 and artemisone to brincidofovir, to arrive at instant claims 1 and 15. One of ordinary skill in the art would have been motivated to make such modification, 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, 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 combination of artemisone and letermovir or brincidofovir, to treat herpesvirus or human cytomegalovirus.
Moreover, 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.
On pg. 9, Remarks, Applicant argues that the synergy recited in claim 1 is not a desired property, but rather an experimentally established effect and that Example 1 provides statistically significant evidence that the claims pairs of antiviral compounds provide a synergistic antiviral effect at the claimed concentration range in vitro. On pg. 10, Remarks, Applicant argues that the present application shows a profound synergistic anti-HCMV effect, and that amended claim 1 recites now a narrow range of ratios in which the synergy exist.
This argument has been fully considered, but is not found persuasive.
Regarding claim 1, it is respectfully pointed out that the “viral infection” is not limited to HCMV, as argued, and that the ratios are not narrow, as argued, but are broad, “the molar ratio of artemisone and letermovir is in the range of from 2000:1 to 20:1 and the molar ratio of artemisone to brincidofovir is in the range of from 10000:1 to 100:1.”
Regarding Example 1, the specification states that stocks of 10mM artemisone, 1mM brincidofovir and 10mM letermovir were prepared in DMSO or H2O ([0109]). Thus, Example 1 provides a single, in-vitro example of a 1:1 ratio of artemisone to letermovir and a 10:1 ratio of artemisone to brincidofovir. However, the instantly claimed ratios are from 2000:1 to 20:1 and from 10000:1 to 100:1, respectively. Thus, Example 1 is not commensurate in scope with instant claims 1 or 15 since the claims encompass a great range of ratios of artemisone to letermovir, and artemisone to brincidofovir, and example 1 only provides a single ratio in each of the claimed ranges, and since the claims recite a method of treating any viral infection, and example 1 only provides data for the treatment of a single viral infection, cytomegalovirus. And while Table 1 ([0121]) provides dates that shows synergisms and the previous paragraphs detail how the synergisms are calculated, Example 1 provides no data on the individual anti-viral effect of artemisone, letermovir, or brincidofovir. As such, it is not possible to determine that the combination of artemisone and letermovir and/or artemisone and brincidofovir do result in an unexpected synergistic effect versus an additive anti-viral effect.
Regarding ranges and unexpected results, Applicant is respectfully reminded that 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. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960), See MPEP 716.02(d).
It is further noted that Example 1 is an in-vitro experiment, and on pg. 9, Remarks, Applicant states, “As also described e.g. in para [0006], sometimes when moving from an in vitro to an ex vivo model, the synergistic effect may disappear, e.g. in Morere et al. It is not possible to establish any kind of prediction regarding the synergistic effect of a combination of compounds.” As such, it appears that Applicant is stating that it is not known if the instantly claimed administration of a ratio of 2000:1 to 20:1 of artemisone to letermovir, or a ratio of 10000:1 to 100:1 of artemisone to brincidofovir, to a subject with a viral infection, would result in a synergistic effect in vivo.
Regarding Applicant’s reference to [0029], [0018], and [0006] of the instant specification, it is noted that none of these paragraphs provide support for a synergistic antiviral effect other than stating that there is one. [0029] is directed toward the structure of letermovir and makes no mention of synergism. [0018] states, “The present invention provides a combination of artemisone with a at least one antiviral compound, wherein such a combination provides a synergistic antiviral effect,” but provides no data. And [0006] states that available anti-CMV drugs for systemic treatment are limited by toxicity, bioavailability, high cost, and teratogenicity.
In view of the above, Applicant’s argument that “the synergy recited in claim 1 is not a desired property, but rather an experimentally established effect,” on pg. 9, Remarks, is not found persuasive.
On pg. 10, Remarks, Applicant argues a) that the amounts cites in Haynes refers to compounds claimed therein, and that the amounts do not refer to additional antiviral drugs such as letermovir and brincidofovir, b) that the range of the concentration is so large that it embraces all feasible concentrations at which any active agent may be administered, c) that Haynes is silent about the amount of additional antiviral drug and does not teach molar ratios, and d) that a person skilled in the art would not have been taught the claimed molar ratio.
These arguments have been fully considered, but are not found persuasive.
It is first noted that the motivation to arrive at the instantly claimed molar ratios is discussed in the above rejections, and discussed in the above arguments.
In US 9,616,067 to Haynes and WO 2013/157005 to Haynes, the following is taught (see above rejections for citations):
-Haynes teaches co-administering an anti-viral drug
-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, such as inhibiting virus activity. Haynes further teaches that the administration regimen 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 human cytomegalovirus (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.
Thus, Haynes clearly teaches molar concentrations, clearly teaches examples of the amounts in which antiviral agents in its formulations are administered (i.e., “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” (Col. 23, line 35-Col. 24, line 6 of ‘067; pg. 34, lines 1-26 of ‘005)), and clearly teaches that it is well known in the art to optimize dosage amounts to arrive at therapeutically effective amounts to treat viral infections.
On pgs. 10-11, Remarks, Applicant states that unexpected results have been demonstrated.
This argument has been fully considered, but is not found persuasive.
Example 1 has been thoroughly discussed above. In summary, Example 1 is not commensurate in scope with either instant claims 1 or 15, and since Example 1 does not provide data on artemisone, letermovir, or brincidofovir, alone, it is not possible to determine if the cited synergistic results are truly synergistic or if they are additive effects. Further regarding Tables 4 and 5 ([0126]-[0127]) in Example 1, it is pointed out that what Applicant points to as a synergistic effect appears to be an additive effect. For example, in Table 4, to achieve 90% inhibition of the virus, a concentration of 7.66 of artemisone is required and a concentration of 0.01 letermovir is required, individually. When combined, a concentration of 7.04 artemisone and a concentration of 1.75 letermovir is required. Thus, the amount of artemisone is decreased while the amount of letermovir is increased. As such, it is not clear how this shows a synergistic effect since the amounts of both artemisone and letermovir are modified. As such, neither Table 4 nor Table 5 are sufficient to demonstrate unexpected results. Moreover, neither Table 4 nor Table 5 are commensurate in scope with the instantly claimed ratio ranges.
It is noted that Example 2, beginning on pg. 41, is directed toward testing the synergistic effect of artemisone and maribavir on an ex-vivo antiviral model. However, maribavir is outside the scope of instant independent claims 1 and 15.
It is lastly noted that the instant, independent claims are directed toward a method of treating any viral disease, but the examples are limited to the treatment of cytomegalovirus.
Regarding unexpected results, MPEP 716.02 states that unexpected results a) are greater than expected results, b) show superiority of a property shared with the prior art, c) exhibit the presence of an unexpected property, and/or d) exhibit the absence of an expected property. MPEP 716.02 additionally states that unexpected results must be commensurate in scope with the claimed invention, provide a comparison with the closest prior art. And specifically regarding ranges, MPEP 716.02(d) 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.”
In summary, in the instant case, a) Example 1 is not commensurate in scope with independent claims 1 or 15, b) it is not possible to determine a synergistic effect since the data in Tables 1, 4, and 5, do not provide comparative data of the individual activity of artemisone, letermovir, or brincidofovir at the same concentrations, and c) a sufficient number of tests both inside and outside the claimed molar ratio range to show the criticality of the claimed range, has not been shown.
For these reasons, the arguments are not persuasive to overcome the rejection.
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, 4-11, 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), as evidenced by PubChem (Brincidofovir, PTO-892),
‘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 (claims 1, 3, 6-7, 9, 11, 14-15).
Regarding claims 1, 8-10, 15-16, and 18 while ‘067 teaches a method of treating herpesvirus, and specifically cytomegalovirus by administering artemisone and an anti-viral, it differs from that of claims 1, 8-10, 15-16, and 18 in that it does not teach letermovir or brincidofovir as the antiviral.
Haynes teaches ganciclovir, foscarnet, cidofovir, valganciclovir, foscarnet, acyclovir, valacyclovir, maribavir, letermovir and brincidofovir (CMX-001) as antivirals for use in its methods (pg. 30, lines 3-18).
As evidenced by PubChem (Brincidofovir), CMX-001 is brincidofovir.
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 select letermovir or brincidofovir of Haynes as the antiviral in the methods of ‘067, to arrive at instant claims 1, 8-10, 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 teaches letermovir and brincidofovir as such anti-viral drugs.
As such, an ordinary skilled artisan would have been motivated to make such selections, to predictably arrive at methods of treating herpesvirus and cytomegalovirus that are therapeutically effective and optimized for anti-viral effect.
Further, regarding claims 1 and 15, while the combination of ‘067 and Haynes teaches a method of treating herpesvirus, and specifically cytomegalovirus by administering artemisone and letermovir or brincidofovir, it differs from that of claims 1 and 15 in that it 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).
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 and artemisone to brincidofovir, in the combined method of ‘067 and Haynes, to arrive at instant claims 1 and 15. One of ordinary skill in the art would have been motivated to make such modification, with a reasonable expectation of success, because:
-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,
-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, 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 combination of artemisone and letermovir or brincidofovir, to treat herpesvirus or cytomegalovirus.
Regarding claims 4 and 6, ‘067 teaches 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 5, since the combination of ‘067 and Haynes teaches amounts of artemisone and letermovir or brincidofovir to treat viral infections, the limitations of this claim are met. See the interpretation of this claim in the 112(b) section above.
Regarding claim 7, ‘067 claims a composition comprising a artemisone, an anti-viral, and a pharmaceutically acceptable carrier or excipient (claims 1, 9).
Regarding claim 11, Haynes teach methods of treating herpesvirus and specifically HCMV in newborns, pregnant women, and transplant recipients by administering artemisone and letermovir or brincidofovir (pg. 6, lines 14-28; pg. 29, line 24-pg. 30, line 2). As such, it would be reasonably expected that the combined methods of ‘067 and Haynes are effective for treating herpesvirus, and specifically HCMV, in newborns, pregnant women, and transplant recipients.
Claims 1, 4-11, 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. 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), as evidenced by PubChem (Brincidofovir, PTO-892),
‘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 (claims 1, 6-7, 9, 11, 18, 21, 23).
Regarding claims 1, 8-10, 15-16, and 18, while ‘884 teaches a method of treating herpesvirus, and specifically cytomegalovirus by administering a composition comprising artemisone, a pharmaceutically acceptable carrier or excipient, and an anti-viral, it differs from that of claims 1, 8-10, 15-16, and 18, in that it does not teach letermovir or brincidofovir as the antiviral.
Haynes teaches ganciclovir, foscarnet, cidofovir, valganciclovir, foscarnet, acyclovir, valacyclovir, maribavir, letermovir and brincidofovir (CMX-001) as antivirals for use in its methods (pg. 30, lines 3-18).
As evidenced by PubChem (Brincidofovir), CMX-001 is brincidofovir.
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 select the letermovir or brincidofovir of Haynes as the antiviral in the methods of ‘884, to arrive at instant claims 1, 8-10, 15-16, and 18. 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 teaches letermovir and brincidofovir as such anti-viral drugs.
As such, an ordinary skilled artisan would have been motivated to make such selections, to predictably arrive at a method of treating cytomegalovirus that is therapeutically effective and optimized for an anti-viral effect.
Further regarding claims 1 and 15, while the combination of ‘884 and Haynes teaches a method of treating herpesvirus, and specifically cytomegalovirus by administering artemisone and letermovir or brincidofovir, it differs from that of claims 1 and 15 in that it 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).
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 and artemisone to brincidofovir, in the combined method of ‘884 and Haynes, to arrive at instant claims 1 and 15. One of ordinary skill in the art would have been motivated to make such modification, with a reasonable expectation of success, because:
- 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,
-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, 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 combination of artemisone and letermovir or brincidofovir, to treat herpesvirus or cytomegalovirus.
Regarding claims 4 and 6, ‘884 teaches 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 5, since the combination of ‘884 and Haynes teaches amounts of artemisone and letermovir or brincidofovir to treat viral infections, the limitations of this claim are met. See the interpretation of this claim in the 112(b) section above.
Regarding claim 7, the combination of ‘884 and Haynes claims a composition comprising a artemisone and letermovir or brincidofovir, and a pharmaceutically acceptable carrier or excipient.
Regarding claim 11, Haynes teach methods of treating herpesvirus and specifically HCMV in newborns, pregnant women, and transplant recipients by administering artemisone and letermovir or brincidofovir (pg. 6, lines 14-28; pg. 29, line 24-pg. 30, line 2). As such, an ordinary skilled artisan would predictably expected the combined methods of ‘884 and Haynes to treat HCMV in newborns, pregnant women, and transplant recipients.
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.
Response to Arguments
On pg. 11, Remarks, Applicant requests that these rejections be held in abeyance.
This request is acknowledged.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LAUREN WELLS/Examiner, Art Unit 1622