DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/9/26 has been entered.
Claims 1-29 are pending. Claim 28 has been withdrawn. Claims 1-27, 29 are examined herein.
Applicant argues that the rejections of record should be withdrawn for at least the reasons set forth in the Argument sections of the Appeal Brief previously filed on 11/15/24. Since no new arguments are presented, the same response to arguments will apply. Accordingly, the rejections of record are maintained for reasons of record and repeated below for Applicant’s convenience.
All claims are drawn to the same invention claimed in the application prior to the entry of the submission under 37 CFR 1.114 and could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 extension fee 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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 8-9, 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Toure et al. (Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated Plasmodium falciparum malaria: a phase II, multicentric, open-label study,” Malaria Journal, 2015, vol. 14, no. 469, pp. 1-12, of record).
Toure et al. teach the efficacy and safety of a fixed dose combination of arterolane maleate 37.5 mg and piperaquine 187.5 mg dispersible tablets in paediatric patients aged 6 months to 12 years, which were administered once a day for three days. This combination effectively cures malaria and attains acceptable level of cure by day 28 (abstract). Previously, 150 mg of arterolane maleate and 750 mg of piperaquine phosphate showed anti-malarial efficacy and safety in 240 adult patients with acute uncomplicated falciparum malaria (page 2, left column, third paragraph). The World Health Organization recommends artemisinin combination therapy (ACT) as the first-line treatment for acute uncomplicated falciparum malaria in all endemic regions (page 2, left column, first paragraph). Administration of ACT to infants and small children can be difficult and time consuming. Specifically formulating anti-malarials for this vulnerable population is vital to ease administration and help ensure that an accurate dose is received. Realizing this need, a fixed dose combination of arterolane maleate 37.5 mg and piperaquine 187.5 mg dispersible tablets has been formulated (page 2, right column, second paragraph). The minimum body weight of the subjects was 5 kg (page 3, left column, third paragraph). The mean body weight of the subjects was 18.5 kg with a 7 kg min and 36 kg max (Table 1 on page 7).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 5-7, 10-23, 25-27, 29 are rejected under 35 U.S.C. 103 as being unpatentable over Toure et al. (Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated Plasmodium falciparum malaria: a phase II, multicentric, open-label study,” Malaria Journal, 2015, vol. 14, no. 469, pp. 1-12, of record), as applied to claims 1-4, 8-9, 24, in view of Enose et al. (WO 2013/008218, of record).
The instant claims are directed to a composition comprising arterolane, piperaquine, and mefloquine in the claimed dosage amounts in accordance with the claimed body weights of the patients.
Toure et al. teach as discussed above, however, fail to disclose the claimed dosage amounts in accordance with the claimed body weights of the patients.
Enose et al. teach stable oral dosage forms of the spiro 1,2,4-trioxolane antimalarial, arterolane (active compound I), and piperaquine for treating malaria (title, abstract, and claims 23-24). Preferred dosages for trioxolanes range from 0.1-1000 mg/kg/day and in particular 1-100 mg/kg/day (page 3, lines 20-29). In another preferred embodiment, the active compound I may be in an amount from 5-25%, and piperaquine in an amount from 40-80% based on the total weight of the dosage form (page 7, lines 13-22). Put another way, active compound I and piperaquine are in a weight ratio of about 1:1 to about 1:10. Yet, in another embodiment, active compound I may be present in a dose range of 100-300 mg and piperaquine present in a dose range of 700-850 mg (page 8, lines 1-5). Enose et al. also discloses oral dosage forms of the active compound I in a unit dose of 100, 150, or 250 mg and piperaquine present in a unit dose of 750 mg once a day for 3 days (page 14, lines 1-17). Various body weights are taught for subject, for example an adult having body weight over 35 kg or an adult having body weight between 36-75 kg (page 4, lines 16-24). Finally, Enose et al. teach that the dosage forms may also include one or more other antimalarial drugs, such as mefloquine (page 6, lines 3-5; page 13, lines 3-4).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have formulated a composition comprising arterolane and piperaquine in the method of treating malaria, as taught by Toure et al. in the claimed dosage amounts in accordance with the claimed body weights of the patients, as taught by Enose et al.
A person of ordinary skill in the art would have been motivated to formulate a composition comprising arterolane and piperaquine in the claimed dosage amounts in accordance with the claimed body weights of the patients because the dosage amounts of both arterolane and piperaquine, as taught by Enose et al., encompass the claimed dosage amounts in accordance with the claimed body weights. For example, arterolane is taught to be in a dosage amount of 100-300 mg. Piperaquine is taught to be in a dosage amount of 700-850 mg. Dosages for arterolane can also be calculated from body weight using the range from 0.1-1000 mg/kg/day and in particular 1-100 mg/kg/day, which also encompass the instant claims. Ratios of arterolane to piperaquine range from 1:1 to 1:10. Furthermore, while Toure et al. teach young children, which encompasses lower claimed body weights, Enose et al. teach full adults, which encompass the higher claimed body weights. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success in formulating the claimed dosage amounts for arterolane and piperaquine for the method of treating malaria. Finally, it is also obvious for the skilled artisan to include instructions on how to administer the pharmaceutical composition comprising arterolane and piperaquine so as to safely and effectively treat malaria in a patient in need thereof.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to have formulated a composition comprising arterolane and piperaquine in the method of treating malaria, as taught by Toure et al. with mefloquine, as taught by Enose et al.
A person of ordinary skill in the art would have been motivated to formulate a composition comprising arterolane, piperaquine, and mefloquine because all three active agents are individually known to be useful for treating malaria. Further, Enose et al. teach the use of other antimalarials in combination with arterolane and piperaquine. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success in treating malaria by the therapeutically additive effect of combining arterolane, piperaquine, and mefloquine.
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... The idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Response to Arguments
With respect to the 102 rejection, Applicant argues that Toure does not explicitly teach a body weight-based dosage regimen. It is argued that just because in a certain circumstance the dosage happens to satisfy the numerical limits doesn’t mean that Toure inherently discloses the limits since the body weight-based dosage doesn’t happen under every circumstance. The study in Toure suggests a mean body weight and a maximum and minimum weight range and a dosage range for Arterolane and Piperaquine. If this range is used, it does not inherently result in a body weight-based dosage regime. Moreover, Toure teaches a dose regimen based upon patient age and not weight.
This is not persuasive because Toure clearly teaches a preferred embodiment in their study that meets the limitations of claim 1, despite the fact that the reference may or may not describe it as a body weight-based dosage regime. Under the results section on page 5, Toure discloses that 141 patients with malaria were enrolled in the study to receive 37.5 mg of Arterolane and 187.5 mg of Piperaquine. Table 1 shows that the average weight of the patients was 18.5 kg with a minimum of 7 kg and a maximum of 36 kg. This demographic data clearly shows that among the 141 patients, there was at least one patient weighing the minimum 7 kg and at least one patient weighing the maximum 36 kg. Since all of the 141 patients were administered Arterolane and Piperaquine, the body weight-dosing regimen for the patient weighing 7 kg can be easily calculated as follows:
Arterolane: 37.5 mg / 7 kg = 5.35 mg/kg
Piperaquine: 187.5 mg / 7 kg = 26.8 mg/kg
Therefore, it is respectfully submitted that the body weight-dosing regimen of 5.35 mg/kg of Arterolane as taught by Toure reads on and is within the claimed range of 3 to 6.5 mg/kg of Arterolane in claim 1. Similarly, the body weight-dosing regimen of 26.8 mg/kg of Arterolane as taught by Toure reads on and is within the claimed range of 15 to 32 mg/kg of Piperaquine in claim 1. Furthermore, attention is drawn to instant claim 2, which recites “wherein the dosage is administered in a fixed dose pharmaceutical composition in accordance with a body weight of a patient,” which is precisely how the aforementioned Toure calculations were based on. Finally, Applicant is reminded that every circumstance (or patient in the study) need not read on the claims as long as there is at least one preferred embodiment or patient, in this case, that meets the limitations of claim 1.
With regard to the 103 rejection, Applicant argues that Enose does not teach or suggest a body weight-based dosage regimen. By teaching only 100-300 mg of Arterolane dose range and 700-800 mg of Piperaquine dose range, Enose does not alleviate the deficiencies of Toure. Applicant goes further to argue that Enose’s teaching of a dose of 0.1-1000 mg/kg/day and 1-100 mg/kg/day are not enabled because they are no examples or enabling disclosure. In support, attention is drawn to Enose on page 14, last paragraph, which teaches that the “dosing regimen of the present invention is suitable for all patients aged from 12 to 65 years and thus eliminates the need for calculating dose based on individual weight parameters.” Applicant claims that they have found a new dosing regimen to meet the challenges of a serious global public health concern due to malaria infection.
This is not persuasive because Applicant’s interpretation of the Enose reference is incomplete. While Enose teaches administering fixed dosage amounts for trioxolane derivatives, such as Arterolone, the reference also teaches that body-weight dosing is well-known in the art and has been traditionally used against malaria infections. Corroboration is found on page 3, lines 24-26, where it states “In general, the therapeutic dose of trioxolane derivative may range between about 0.1-1000 mg/kg/day, in particular between about 1-100 mg/kg/day.” Applicant has not provided any evidence or factual data that this teaching regarding body-weight dosing is not enabled. In the absence of any evidence, the fact remains that Enose clearly teaches not only body-weight dosing, but also dosing ranges that encompass the claimed ranges. Therefore, there is no teaching away from body-weight dosing regimens in Enose.
In response to Applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Finally, Applicant argue that the inventors developed the proposed body weight dosing regimen based on successful experimental outcomes in The Nasa Declaration under 37 CFR 1.132 filed 12/19/23, which demonstrates that this body weight dosing regimen is not an obvious extension of the prior art.
This is not persuasive because, as stated in the last office action, claims 5-7, 10-23, 25-27, 29 are rejected by Toure et al., as applied to claims 1-4, 8-9, 24, in view of Enose et al. Since claims 5-7, 10-23, 25-27, 29 are dependent on claims 1-4, 8-9, 24, which themselves are rejected in an anticipatory 102 rejection, this Nasa Declaration is moot, because declarations cannot overcome anticipatory 102 rejections.
Nonetheless, the declaration is not persuasive. The only section that is relevant is the third part, which evaluates the impact of lower dose of piperaquine phosphate in Synriam, compared to the dose recommended by WHO in DHA PQP. The other sections have to do with evaluating cross-resistance and re-analysis of parasitic clearance data.
The declaration states that the optimized body weight based dosage would be 4 mg/kg arterolane and 18 mg/kg piperaquine. The clinical trial in coastal Kenya children explored higher dose regimen, which reached the target efficacious exposure of arterolane as predicted by modelling. In summary, Synriam Plus is a clinically non-inferior alternative to artemether-lumefantrine in the treatment of uncomplicated malaria. The declaration concludes that Synriam Plus with its optimized weight based dosage, establishes it to be an efficacious, safe, and affordable alternative to ACTs for the first line treatment of uncomplicated malaria in adults and children.
This is not persuasive because the declaration is merely showing that the invention works as intended. One of ordinary skill in the art knows how to optimize dosages. There is no data or argument to corroborate any showing of unexpected or surprising results. Regardless, Applicant is reminded that Toure clearly teaches a fixed dose combination of 5.35 mg/kg/day for arterolane maleate and 26.8 mg/kg/day for piperaquine, which meet the limitations of claim 1. Finally, the argument comparing Synriam Plus with artemether-lumefantrine is irrelevant, since artemether-lumefantrine is not even mentioned in the cited prior art references.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
THIS ACTION IS MADE FINAL. 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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yong S. Chong whose telephone number is (571)-272-8513. The examiner can normally be reached Monday to Friday: 9 AM to 5 PM EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam Milligan, can be reached at (571)-270-7674. The fax phone number for the organization where this application or proceeding is assigned is (571)-273-8300.
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/Yong S. Chong/Primary Examiner, Art Unit 1623
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