DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Priority
This application is a continuation of U.S. Application No. 14/342,889 filed on March 5, 2014, which is a national stage entry of PCT/JP2012/072544 filed on September 5, 2012 which claims foreign priority based on an application filed in Japan on September 5, 2011. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 14/342,889, filed on March 5, 2014.
Response to Amendment
Applicant’s amendment filed on December 1, 2025 amending claim 1 has been entered. Claims 1-20 are currently pending and presented for examination.
Response to Arguments
Applicant's arguments filed December 1, 2025 have been fully considered but they are not persuasive.
With respect to the rejection under 35 USC 101, Applicant argues that the Office Action acknowledges that the claims include a process of administering 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to a patient in a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more and is determined to be Definite ALS or Probable ALS according to the revised El Escorial diagnostic criteria, not "treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis, comprising only evaluating a patient in need thereof for efficacy of 3-methyl-1-phenyl-2- pyrazolin-5-one or a physiologically acceptable salt thereof based on ALSFRS-R and %FVC." Applicant therefore argues that the subject matter recited in Claim 1 is directed to a process of treating an ALS patient by administering 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof, which is not a natural phenomenon or an abstract idea.
These arguments are found not persuasive since the rejected claims are drawn to two embodiments wherein one embodiment is drawn to the judicial exception of a natural phenomenon or an abstract idea. The first embodiment is a method for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis, comprising: measuring %FVC of a patient in need thereof; measuring ALSFRS-R of the patient in need thereof; and administering an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof in a range of 15 mg to 240 mg per dose to the patient in need thereof wherein the patient is in a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more. The second embodiment encompassed by the claims is a method for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis, comprising only measuring %FVC and ALSFRS-R in a patient wherein it has been determined that the patient scores less than two points from each of all items constituting ALSFRS-R in combination with less than 80% in %FVC. In these patients, the administration of an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof in a range of 15 mg to 240 mg per dose would not occur since the criteria has not been met in this patient population. Thus the claims are rejected under 35 USC 101 because of the second embodiment encompassed by the claims which is drawn to merely measuring %FVC and ALSFRS-R in a patient with ALS.
Therefore, since said second embodiment is still encompassed by the currently amended claims, the previous rejection under 35 USC 101 is hereby maintained and reproduced below.
With regard to the rejection under 35 USC 103, Applicant argues that Yoshino et al., the Yoshino article 2003, the Yoshino article 2006, the Traynor article, the Cedarbaum article and their combinations do not teach or suggest "measuring %FVC of a patient in need thereof; measuring ALSFRS-R of the patient in need thereof; and administering an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof in a range of 15 mg to 240 mg per dose to a patient in need thereof if the patient is in a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more, wherein the administering comprises administering the effective amount to the patient for a plurality of administration periods establishing an initial administration period, an initial drug holiday period, and a number of doses per day based on a condition or conditions of the patient, and repeating an administration period and a drug holiday period such that the patient undergoes at least three administration periods including the initial administration period such that the specific patient group scores 2.5 points or better than a placebo administration group with respect to ALSFRS-R when the plurality of administration periods is six administration periods establishing an initial 14-day administration period and an initial 14-day drug holiday period, and thereafter, repeating the administration period of 10 out of 14 days and the drug holiday period of 14 days" as recited in amended Claim 1.
Applicant argues that "The PTO must make findings of relevant facts, and present reasoning in sufficient detail so the court may conduct meaningful review of the agency action." Applicant argues "In rejecting claims under 35 U.S.C. § 103, the examiner bears the initial burden of presenting a prima face case of obviousness. Only if that burden is met, does the burden of coming forward with evidence or argument shift to the applicant." In re Rifckaert, 9 F.3d 1531, 1532 (Fed. Cir. 1993) (citations omitted).
Applicant argues that the Examiner's initial burden of proof is heavy because Claim 1 requires a significant level of improved effectiveness when edaravone is administered to a specific select group of ALS patients in an amount in a range of 15 mg to 240 mg per dose. Applicant states under oath (Spec., p. 24): Accordingly, in the case of specific patients in the present invention, the risk of such death or tracheostomy can be reduced by 3.5% or more, and thus, this is greatly advantageous for patients with amyotrophic lateral sclerosis.... Thus, excellent results could be obtained, in which these values were 3 times or more greater than the between-group difference obtained in the case of not specifying patient groups ....It was found that these patient groups ...each had a significant difference, in comparison with the placebo administration group. Moreover, the separate Declarations of record by Soubue and Sakata state that the claimed significant improvement would not have been expected and would have been surprising in view of the prior knowledge in the art.
Applicant argues that Yoshino et al., the Yoshino article 2003, the Yoshino article 2006, the Traynor article and the Cedarbaum article do not teach or reasonably suggest the claimed level of significantly improved effectiveness required when administering edaravone to the specifically identified group of select ALS patients as recited in Claim 1. Moreover, Yoshino et al., the Yoshino article 2003, the Yoshino article 2006, the Traynor article and the Cedarbaum article do not show that administration of edaravone to the claimed select group of ALS patients would achieve a difference of 2.5 or better than a placebo administration group with respect to ALSFRS-R in a select group of ALS patients than it would be if the same amount is administered to ALS patents outside the claimed select group by the same regimen.
Applicant argues that the declaratory evidence of record shows, and Applicant's Specification teaches at page 34, that the improved level of effectiveness of the same drug administered in the same amount and in the same manner to the claimed select group of ALS patients is "greatly advantageous" for patients with ALS , patentably "significant," unexpected, and surprising, and cannot be ignored, especially when the unexpected results are expressly claimed.
Thus Applicant argues that Yoshino et al., the Yoshino article 2003, the Yoshino article 2006, the Traynor article and the Cedarbaum article do not disclose or suggest establishing an initial administration period, an initial drug holiday period, and a number of doses per day based on a condition or conditions of the claimed select group of patients scoring two or more points from each of all items constituting ALSFRS-R with %FVC of 80% or more, and administering edaravone in an amount in the range of 15 mg to 240 mg per dose to the claimed select group of patients, much less achieving a difference of 2.5 or better than a placebo administration group with respect to ALSFRS-R when the same amounts are administered by the claimed regimen. Nor do the references reasonably suggest the level of improved treatment for ALS which Claim 1 requires for any specific group of definite or probable ALS patients. Rather, logic suggests that greater success in treating symptoms of ALS could be expected when administering edaravone to patients showing greater ALS symptoms than to patients showing lesser ALS systems.
Applicant further argues that in addition to showing that there was a suggestion or motivation to modify the prior art to arrive at the claimed invention, to establish a prima face case of obviousness, the Examiner must demonstrate that there was a reasonable expectation of achieving the success claim 1 requires. In re Vaeck, 947 F.2d 488, 493 (Fed. Cir. 1991). Applicant argues the requisite expectation of success is NOT found anywhere in the prior art.
With regard to the rejection based on the non-statutory double patenting, Applicant argues that none of U.S. Patent No. 6,933,310 B1, Yoshino article 2006, the Traynor article, and the Cedarbaum article recognizes or reasonably suggests the currently claimed difference of 2.5 or better than a placebo administration group for the claimed select group of patients through the administration of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof based on the claimed regimen. As such, for the same reasons stated in response to the rejections under 35 U.S.C. § 103 in view of combined prior art teachings, Applicant argues the rejection should be withdrawn.
These arguments are found not persuasive because with regard to Applicant’s argument that the references do not teach or suggest measuring %FVC of a patient in need thereof and measuring ALSFRS-R of the patient in need thereof, which are newly added limitations, Yoshino et al. specifically teaches determining the ALSFRS-R score starting at 6 months prior to treatment, during treatment and after the end of treatment [0122]. Yoshino et al. teaches treating patients with an ALSFRS-R score of 38 just prior to treatment [0122]. Yoshino et al. teaches that the term %FVC stands for the percent predicted forced vital capacity and is generally used as an index in a method for objectively evaluating respiratory function in ALS patients [0135]. Yoshino et al. specifically teaches measuring the %FVC prior to treatment, during treatment and after the end of treatment ([0135]-[0136]). Thus Yoshino et al. specifically teaches evaluating an ALS patient based on measuring ALSFRS-R and %FVC.
Furthermore, with regard to the additional limitations claimed including administration of edaravone to the claimed patient population in an amount in a range of 15 mg to 240 mg per dose, Yoshino 2008 specifically exemplifies the treatment of ALS comprising the administration of edaravone wherein 30 mg or 60 mg of edaravone was administered for 14 consecutive days followed by a 2 week holiday period and thereafter administration was carried out for 10 days out of 14 days followed by a 2 week holiday period ([0120] and [0121]). Yoshino 2006 teaches treating patients diagnosed with sporadic amyotrophic lateral sclerosis (SALS) or familial amyotrophic lateral sclerosis (FALS) with either 30 or 60 mg of edaravone injections every day for two weeks and then patients were observed for two weeks without edaravone treatment (page 248). Yoshino 2003 teaches administration of 30 mg/day of edaravone to patients for 14 days followed by 14 days wherein the drug was withheld (pages 12-13 of Translation).
Thus, all of the Yoshino references specifically teach administration of edaravone within the claimed range. Thus, by following the teachings and suggestions of the prior art, one would necessarily administer edaravone at an optimal dosage within the range as claimed which will necessarily result in the patient scoring 2.5 points or better than a placebo group. Therefore, in response to applicant's argument that the prior art does not teach or suggest that administration of edaravone would lead to the patient scoring 2.5 points or better than a placebo group, the fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
With respect to the claimed patient population, it is maintained that each of the references cited provides a reasonable expectation of improved success in treating the claimed patient population with ALS comprising the administration of edaravone. Thus, the references cited specifically suggests that the claimed patient population would have improved success by using edaravone to treat ALS.
First the cited references teach and suggest that all patients with ALS will benefit from treatment with edaravone. The primary references (U.S. Patent No. 6,933,310 B1 to Ikeda and Yoshino ‘2008) both claim a method of treating ALS in all patients in need thereof comprising the administration of the claimed compound (edaravone). Likewise, the primary reference Yoshino ‘2006 specifically states in almost all patients, CSF 3NT, a marker of oxidative stress, was markedly reduced to almost undetectable levels at the end of the six-month treatment period and data from the study suggest that edaravone is safe and may delay the progression of functional motor disturbances by reducing oxidative stress in ALS patients (see abstract). Therefore, the primary references do not teach or suggest that the administration of edaravone would not be useful in Applicant’s claimed patient population who score two or more points from each of the items of the ALSFRS-R and has a %FVC of 80% or more. Thus, there is no reason why a person of ordinary skill in the art would not have treated the claimed patient population in view of Ikeda and Yoshino 2008 which specifically claim treating ALS in a patient consisting essentially of the administration of edaravone and in view of the teachings of Yoshino 2006 which specifically demonstrate treating patients with ALS comprising the administration of edaravone. Thus, each of the primary references provide a reasonable expectation of success in treating ALS with edaravone regardless of what stage the patient is in since each of the references indicate promising results for ALS. Moreover, none of the references cited provide any reason to doubt the therapeutic benefit of edaravone in any particular ALS group.
Second, Yoshino 2003 and Yoshino 2006, clearly suggest that patients in the earlier stages of ALS may have an increased benefit in treatment with edaravone. Yoshino 2003 teaches that administration of edaravone at the initial phase of the disease when peroxynitrite is eliminated early would make it possible to expect greater clinical validity (page 17 of Translation). Yoshino 2003 teaches that groups having ALSFRS of 40 or more points which do not require intervention in daily life tend to have a smaller decline in the score 6 months later (page 17 of Translation). Moreover, Yoshino 2006 specifically demonstrates in Figure 1 that those patients starting treatment with a higher ALSFRS-R total score tended to have smaller reductions in ALSFRS-R scores following treatment.
Thus Yoshino 2003 and Yoshino 2006 specifically teach and suggest that the claimed patient population would have increased treatment success since the claimed patient population is consistent with a patient in the earlier stages of ALS since Cedarbaum et al. teaches that scores of less than 2 would require intervention in daily life. For example, a person with a score of 1 in category 6 would need an attendant for self-care, if a person scores a 1 in category 9 they would need assistance with climbing stairs, etc. Moreover, a patient having a %FVC of 80% or more would be considered having a normal %FVC and as such would not require intervention and thus would be consistent with a patient in the beginning stages of ALS. Thus, treating a patient who is determined to be definite or probable ALS according to the revised El Escorial diagnostic criteria and scores two or more points from all items of the ALSFRS-R and the %FVC of 80% or more as claimed in the instant application is rendered obvious in view of the cited prior art teachings. It would have been obvious to a person of ordinary skill in the art that a patient in the earlier phases of the disease and not requiring intervention in daily life as taught by Yoshino 2003 and Yoshino 2006 and also having a %FVC of 80% or more as claimed in the instant application and thus having no significant loss in respiratory function would have improved treatment success. Thus, treating a patient who is determined to be definite or probable ALS according to the revised El Escorial diagnostic criteria and having a score of 2 or more points and also having a %FVC of 80% or more as claimed with edaravone and expecting greater clinical validity is rendered obvious in view of the references cited.
Therefore, even though Applicant has found a specific subpopulation that responds better to treatment than others with ALS, a prima facie case of obviousness can still be established since the prior art does not discourage a skilled artisan from treating any particular patient population with ALS, especially a patient in the earlier stages of the disease without significant loss of function and with limited loss of respiratory function. Thus, it is clear that edaravone delays the progression of ALS symptoms and as such one would have been motivated to begin treatment early, prior to advanced deterioration and significant loss of respiratory function, with a reasonable expectation of improving treatment outcome. Thus, Applicant’s results are not considered surprising nor unexpected in view of the state of the art at the time of the instant invention.
Thus it is maintained that Applicant’s claimed patient population is consistent with a patient in the early stages of the disease without any significant loss of respiratory function and it would have been obvious to a person of ordinary skill in the art to administer edaravone to said patient population to delay the progression of ALS symptoms, and thus arrive at an amount of edaravone as claimed which would result in the patient scoring 2.5 points or better than a placebo administration group as well as the risk of death or tracheostomy by ALS is reduced by at least 3.5% as compared to a patient outside the claimed population. Moreover, it would not have been considered surprising nor unexpected that said claimed patient population responds better to treatment given the teachings of Yoshino 2006 which specifically demonstrates in Figure 1 that those patients starting treatment with a higher ALSFRS-R total score tended to have smaller reductions in ALSFRS-R scores following treatment.
With regard to Applicant’s argument that the declaratory evidence of record shows, and Applicant’s Specification teaches at page 34, that the improved level of effectiveness of the same drug administered in the same amount and in the same manner to the claimed select group of ALS patients is “greatly advantageous” for patients with ALS, patentably “significant,” unexpected, and surprising, and cannot be ignored, especially when the unexpected results are expressly claimed (see page 13 of Applicant’s remarks), Applicant’s evidence presented in the declarations under 37 CFR 1.132, are found not persuasive in overcoming any rejection of record for reasons or record.
The first Sakata Declaration does not establish “a lack of efficacy” since Mr. Sakata does not even conclude there was a demonstrated “lack of efficacy” of edaravone. Instead, Sakata’s conclusion is directed to whether the data evaluated supports categorizing patients into subpopulations for the purposes of evaluating the effect of an ALS drug. (Sakata Declaration 1 paragraph 14; Sakata Declaration 2 paragraph 12.)
With respect to the assertion in the Sakata 2 declaration that the results from the confirmatory study invalidate the earlier speculations found in the 2003 Yoshino article and the 2006 Yoshino article as to the efficacy of edaravone for the patients in the earlier stages, (Sakata Declaration 2 paragraph 16), in arriving at this conclusion, Sakata only considered the changes in ALSFRS-R scores compared to placebo, not CSF 3NT measurements. Yoshino ‘2006 specifically states “To support the suggested efficacy of edaravone, we therefore looked for changes in oxidative stress in CSF of the treated patients, using 3NT as a marker. A decrease in 3NT levels in the patient’s CSF would be consistent with the known action mechanism of the drug, and could plausibly be expected to benefit patients. In almost all subjects, 3NT levels measured at the end of the sixth cycle of administration were markedly reduced, and were close to or below the threshold of detection.” (Yoshino 2006 page 250). In conclusion, Yoshino 2006 states: “Accordingly, the marked reduction of 3NT seen in the present study suggests that the free radical scavenger edaravone almost completely eliminated oxidative stress in the spinal cord of ALS patients (page 250).
Moreover, Yoshino ‘2003 further teaches that peroxynitrite, and other free radicals play a great role in the pathology of the disease and the effect of the drug is not clear in groups of patients where progress of the disease is quick which suggests that in advanced stages of the disease, factors other than radicals causing cell death of many motor neurons contributes to the pathology (page 15). Furthermore, the conclusion in Yoshino 2003 that “the group having an ALSFRS of 40 or more points which did not require intervention in daily life tended to have a smaller decline in the score 6 months later” and which is an observation in Yoshino 2003 made after suggesting that “administering this drug at the initial phase of the disease when peroxynitrite is eliminated early would make it possible to expect greater clinical validity” (Yoshino 2003 page 17) is not undermined by the “confirmatory study.” That is because the “Between-group Difference” for “the sub-population of patients who scored the total of 41 or more on ALSFRS-R” was 0.66 and for those “who scored the total of less than 41” it was 0.28. (Sakata Declaration 2 paragraphs 10-11.) This confirmatory data, thus, is in accord with Yoshino 2003’s observation of a smaller decline in groups having a higher ALSFRS score and not requiring intervention in daily life.
Second, the data does not establish lack of efficacy of edaravone. The reported data is simply the change in ALSFRS-R score from start of edaravone administration until end of treatment compared to placebo (Sakata Declaration 1 paragraphs 12-13). The ALSFRS-R assesses behavioral or functional activity on a scale of 0-4, which scores are subjective measures unlike, for example, the measure of CSF-3NT before and after treatment. However, even as to these subjective measures, the data reported demonstrates that in groups with an ALSFRS score of 41 or more before initiation there was a reduction in the rate of decline of ALSFRS-R score during the six-month treatment period compared to placebo, albeit a between-group difference of less than one. (Sakata Declaration I paragraph 12). There was also a slight decrease in the subjective measures of the ALSFSR- R score in patients with a score of less than 41 before initiation of treatment. (Sakata Declaration I paragraph 13.) Consequently, even these subjective measures demonstrate efficacy in suppressing disease progression, i.e., treatment.
In any event, although it is true that Yoshino 2006 does not teach, expressly or inherently, that the ALS patients treated had the ALSFRS-R scores recited in the claim or the forced vital capacity (FVC) claimed, there is nothing in either Yoshino 2006 or Ikeda that would lead one of ordinary skill in the art not to expect at least a reduction in the level of CSF 3NT, which would indicate a reduction in oxidative stress of the patient population having the claimed ALSFRS-R scores and FVC. That is because CSF 3NT is a marker of oxidative stress (indicative of oxidative cellular damage) in ALS no matter what stage of the disease. (See Yoshino 2006 page 247 (“oxidative stress has been considered to contribute to the pathogenesis of ALS”).) And edaravone is a free radical scavenger that Applicant does not argue would not have been reasonably expected to cause a decline in CSF 3NT regardless of the stage of ALS. In sum, Ikeda and Yoshino 2006 provide a reason to treat all patients with ALS with a reasonable expectation of success of achieving a decline in CSF 3NT and thus result in a therapeutic benefit to the patient, including those determined to fit within the population identified in the claims.
“To be sure, [i]t is well-settled that a narrow species can be non- obvious and patent eligible despite a patent on its genus.” Prometheus Labs., Inc. v. Roxane Labs, Inc., 805 F.3d 1092, 1098 (Fed. Cir. 2015) (citation omitted). “The genus-species distinction may have particular relevance in the field of personalized medicine, where, for example, a particular treatment may be effective with respect to one subset of patients and ineffective (and even harmful) to another subset of patients.” Id. (emphasis added).
Such is not what is adduced by the evidence here. The fact that Sakata concluded that one could not confirm efficacy of edaravone on the sub-populations classified as 1 or 2 under the Japanese ALS severity classification solely by analysis of differences between ALFSRS-R scores before initiation of treatment and end of treatment when compared to placebo does not address a lack of efficacy of the drug in treating ALS of those patient populations, nor does it address whether CFS 3NT was reduced in this population. (See, e.g., Sakata Declaration 2 paragraphs 6-9.) And, that Sakata concluded “no meaningful guidance” was provided in analyzing ALSFRS-R differences between treated and placebo populations who began treatment with either ALSFRS-R 41 and above or less than 41 “for purposes of evaluating the effect of an ALS drug with patients in clinical trials” also does not address a lack of efficacy of the drug in treating ALS of those patient populations, nor does it address whether CFS 3NT was reduced in this population. (Sakata Declaration 1 paragraph 14; Sakata Declaration 2 paragraph 12.)
Moreover, while evidence of unexpected treatment results would be another way to demonstrate a conclusion of obviousness is inappropriate with respect to the patient subset set forth in Appellant’s claims, Prometheus, 805 F.3d at 1098; In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995) (“One way for a patent applicant to rebut a prima facie case of obviousness is to make a showing of ‘unexpected results,’ i.e., to show that the claimed invention exhibits some superior property or advantage that a person of ordinary skill in the relevant art would have found surprising or unexpected.”), Applicant has not provided sufficient evidence for the reasons detailed above. Furthermore, Applicant’s expert does not attest to any unexpected or surprising results. Moreover, the Specification does not identify any results as to efficacy among various groups as being surprising or unexpected, and particularly no mention is made as to unexpected efficacy in view of the teaching that edaravone was known to reduce CFS-3NT in almost all patients treated (Yoshino ‘2006 abstract). As explained above, the cited prior art provided an expectation of success that the recited drug would be an effective treatment for ALS.
Likewise, Yoshino ‘2008 provides evidence of a reasonable expectation of success of treating, with edaravone, any patient having ALS, no matter what stage. Yoshino ‘2008 does not provide one of ordinary skill in the art with reason to doubt the therapeutic benefit of edaravone to any particular ALS subpopulation. Nor does Applicant provide sufficient evidence that would give rise to such doubt. Moreover, Yoshino 2003, like Yoshino 2006 supports a reasonable expectation of success in achieving some measure of treatment for all types ALS patients (reduction of CNF 3NT) through the administration of edaravone using the cycle of administration taught in Yoshino 2008. Furthermore, Yoshino 2003 indicates that smaller decline in score of ALSFRS in those who did not require intervention in daily life after 6 months of treatment was observed. (see page 17 of translation). Such patients would necessarily have a score of between 2-4 in most categories of ALSFRS. (See Cedarbaum Table 1.) Thus, Yoshino 2003 provides a reasonable expectation of better success, in terms of smaller decline in ALSFRS score, in patients in an earlier stage of ALS, as would be the status of the subpopulation set forth in the instant claims. In sum, Yoshino 2008 and 2003 provide a reason to treat all patients with ALS, including those determined to fit within the population identified in the instant claims, with a reasonable expectation of success of achieving a decline in CSF 3NT and a reasonable expectation of achieving better results (from Yoshino 2003) in the patient population claimed which the is consistent with a patient in the early stages of the disease. Such a reasonable expectation of success is sufficient to establish prima facie obviousness. In re O’Farrell, 853 F.2d at 903-04; Par Pharm., Inc., 773 F.3d at 1198.
Thus Applicant’s declarations and evidence in the specification is found not persuasive.
Applicant’s arguments with respect to the double patenting rejections are found not persuasive for the same reasons as detailed above.
Thus, for reasons of record and for the reasons detailed above, the previous rejections are hereby maintained and reproduced below.
This action is FINAL.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 6, 14 and 20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a natural phenomenon or an abstract idea without significantly more.
The claims recite a method for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis, comprising: administering an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof in a range of 15 mg to 240 mg per dose to a patient in need thereof if the patient is in a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more, wherein the administering comprises administering the effective amount to the patient for a plurality of administration periods establishing an initial administration period, an initial drug holiday period, and a number of doses per day based on a condition or conditions of the patient, and repeating an administration period and a drug holiday period such that the patient undergoes at least three administration periods including the initial administration period such that the specific patient group scores 2.5 points or better than a placebo administration group with respect to ALSFRS-R when the plurality of administration periods is six administration periods establishing an initial 14-day administration period and an initial 14-day drug holiday period, and thereafter, repeating the administration period of 10 out of 14 days and the drug holiday period of 14 days. The cited claims also comprise evaluating the patient for efficacy of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof based on ALSFRS-R and %FVC; and selecting the patient for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis with 3-methyl-1-phenyl-2-pyrazolin-S-one or a physiologically acceptable salt thereof if the patient is a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more.
The claims are rejected since the claims encompass treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis, comprising only evaluating a patient in need thereof for efficacy of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof based on ALSFRS-R and %FVC; since the claim recites administering 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to the patient, only if the patient is in a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more and is determined to be Definite ALS or Probable ALS according to the revised El Escorial diagnostic criteria. Thus the claims encompass no administration step or no further treatment if it is determined that the patient with ALS does not meet the criteria of scoring two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more and is determined to be Definite ALS or Probable ALS according to the revised El Escorial diagnostic criteria.
This judicial exception is not integrated into a practical application because the claims of the instant application as detailed above encompass non-statutory subject matter because it is not a patent-eligible practical application of a law of nature. The claims are directed to an abstract idea without significantly more since as detailed above they do not require an administration step of the claimed compound if it is determined that the patient with ALS does not meet the criteria of scoring two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more and is determined to be Definite ALS or Probable ALS according to the revised El Escorial diagnostic criteria. Thus, one aspect of the claims only require a method for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis, comprising evaluating a patient in need thereof for efficacy of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof based on ALSFRS-R and %FVC, and therefore are not sufficient to qualify as a patent-eligible practical application. Even though Applicant has discovered the correlation between ALSFRS-R and %FVC and efficacy of 3-methyl-1-phenyl-2-pyrazolin-5-one in the treatment of ALS, and thus takes a human action to trigger the manifestation of the correlation, the correlation exists in principle apart from any human action.
A natural principle is the handiwork of nature and occurs without the hand of man. For example, the disinfecting property of sunlight is a natural principle. The relationship between blood glucose levels and diabetes is a natural principle. A correlation that occurs naturally when a man-made product, such as a drug, interacts with a naturally occurring substance, such as blood, is also considered a natural principle because, while it takes a human action to trigger a manifestation of the correlation, the correlation exists in principle apart from any human action. These are illustrative examples and are not intended to be limiting or exclusive.
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For this analysis, the claims focus on a natural principle since the natural principle is a limiting element or step. Thus, the claims are not directed to a practical application of the natural principle that amounts to substantially more than the natural principle itself.
Eligibility Step 2B: Whether a claim amounts to significantly more.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not include additional elements/steps or a combination of elements/steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied to ensure that the claims amount to significantly more than the natural principle itself.
A claim that focuses on the use of a natural principle must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. See Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71-72, 101 USPQ2d 1961, 1966 (2012)). To show integration, the additional elements or steps must relate to the natural principle in a significant way to impose a meaningful limit on the claim scope. The analysis turns on whether the claim has added enough to show a practical application. See id. at 1968. In other words, the claim cannot cover the natural principle itself such that it is effectively standing alone. A bare statement of a naturally occurring correlation, albeit a newly discovered natural correlation or very narrowly confined correlation, is not sufficient. See id. at 1965, 1971.
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A claim with steps that add something of significance to the natural laws themselves would be eligible because it would confine its reach to particular patent-eligible applications of those laws, such as a typical patent on a new drug (including associated method claims) or a new way of using an existing drug. See id. at 1971; see also 35 U.S.C. 100(b). In other words, the claim must be limited so that it does not preempt the natural principle being recited by covering every substantial practical application of that principle. The process must have additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself. See id. at 1968.
In the instant case, as detailed above, the claims encompass treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis, comprising only evaluating a patient in need thereof for efficacy of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof based on ALSFRS-R and %FVC; since the claims recite administering 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof to the patient, only if the patient is in a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more and is determined to be Definite ALS or Probable ALS according to the revised El Escorial diagnostic criteria. Thus the claims encompass no administration step if it is determined that the patient with ALS does not meet the criteria of scoring two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more and is determined to be Definite ALS or Probable ALS according to the revised El Escorial diagnostic criteria and thus the claims do not require any further steps that integrate the recited judicial exceptions into a practical application of the exception.
For these reasons, when the claims are considered as a whole, the claims do not recite anything significantly more than a judicial exception and therefore are not directed to patent eligible subject matter.
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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 6,933,310 B1 (Provided on IDS dated October 28, 2021 herein referred to as ‘310) in view of Yoshino et al. (2006, Amyotrophic Lateral Sclerosis, 2006, Volume 7, pages 247-251-Provided on IDS dated October 28, 2021); Traynor et al. (Arch. Neurol. 2000, 57, pages 1171-1176-Provided on IDS) and Cedarbaum et al. (1999, Journal of the Neurological Sciences, Vol. 169, pages 13-21).
Although the claims at issue are not identical, they are not patentably distinct from each other because the cited claims of the instant application and the cited claims of ‘310 claim the administration of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) for the treatment of ALS. Although ‘310 does not claim the same cycle regimen as claimed in the instant application or the same patient population as claimed in the instant application, it would have been obvious and within the skill of an ordinary artisan to a optimize a patient’s treatment regimen such that optimal results are achieved. Moreover, it would have been obvious to a person of ordinary skill in the art to treat all patients in need thereof, including all those patients diagnosed with ALS by standard methods known in the art. Thus, treating the patient populations as claimed in the instant application diagnosed with ALS is rendered obvious.
In addition, Yoshino et al. teaches treating patients diagnosed with sporadic amyotrophic lateral sclerosis (SALS) or familial amyotrophic lateral sclerosis (FALS) with either 30 or 60 mg of edaravone injections every day for two weeks and then patients were observed for two week without edaravone treatment (page 248). The drug was then administered again for five days a week, for two weeks, followed by a two-week observation period without edaravone treatment and this treatment observation cycle was repeated five times for a total duration of six months (page 248). Thus Yoshino et al. teaches treating ALS and suppressing disease progression as well as treating symptoms of ALS comprising the administration of edaravone by an initial 14-day administration period and an initial 14-day drug holiday and then repeating an administration period for 10 out of 14 days and a 14-day drug holiday period.
Accordingly, at the time of the instant invention it would have been obvious to a person of ordinary skill in the art to combine the claims of ‘310 which claims treating ALS comprising the administration of edaravone with the teachings of Yoshino et al. which teaches treating patients diagnosed with ALS by an initial 14-day administration period and an initial 14-day drug holiday and then repeating an administration period for 10 out of 14 days and a 14-day drug holiday period.
Cedarbaum et al. teaches that the ALS functional rating scale (ALSFRS) is a validated questionnaire-based scale that measures physical function in carrying out activities of daily living of patients with ALS (page 13). Cedarbaum et al. teaches a revised ALSFRS which adds three evaluation items to replace the breathing scale of the ALSFRS (page 13 and Table 1 pages 14-15). Cedarbaum et al. teaches a score of 0-4 for each of the 12 categories and thus a maximum score would be 48 wherein the patient exhibits no symptoms of ALS. Cedarbaum et al. further teaches patients having a mean ALSFRS-R score of 38.0 points and having a mean %FVC of 87.5 (page 15 Table 2).
Accordingly, at the time of the instant invention, it would have been obvious to a person of ordinary skill in the art to evaluate and treat all patients with ALS accordingly to the teaching of ‘310 such as those taught in Cedarbaum et al. having a mean score of the ALSFRS-R of 38.0, which renders obvious two or more points from all items of the ALSFRS-R, and having a mean %FVC of 87.5 (Table 2 page 15). Thus, treating said patient population as claimed in the instant application and as taught in Cedarbaum comprising the administration of edaravone is rendered obvious in view of the claims of ‘310, which claim the treatment of ALS in patients in need thereof comprising the administration of edaravone. Thus, treating a patient who scores two or more points from all items of the ALSFRS-R and having %FVC of 80% or more as claimed in the instant application is rendered obvious in view of the cited prior art teachings.
Traynor et al. teaches that ALS is a progressive degeneration of upper and lower motor neurons and patients with findings suggestive of ALS are accorded different levels of diagnostic certainty (suspected, possible, probable and definite ALS) by application of a set of defined diagnostic criteria (page 1171). Traynor et al. teaches that the diagnostic criteria was established in 1991 as the El Escorial diagnostic criteria and was revised in 1997 as the Airlie House diagnostic criteria (page 1171).
Even though ‘310 does not specifically claim that the patient was diagnosed as probable or definite ALS by the revised El Escorial diagnostic criteria, it is considered routine practice in the pharmaceutical arts to diagnose a patient prior to treatment. Accordingly, prior to treating the patients based on the method of ‘310, a person of ordinary skill in the art would necessarily diagnose a patient by methods well-known in the art. A person of ordinary skill in the art practicing the invention of ‘310 would have been motivated to diagnose a patient based on techniques well-known in the art such as by the revised El Escorial (Airlie House) diagnostic criteria as taught by Traynor et al. Thus, since the revised El Escorial (Airlie House) diagnostic criteria was a suitable method for diagnosing ALS at the time of the instant invention, it would have been obvious to a person of ordinary skill in the art to diagnose a patient suspected of having ALS by the revised El Escorial (Airlie House) diagnostic criteria with a reasonable expectation of success. Thus, treating a patient having ALS who was diagnosed by the revised El Escorial (Airlie House) diagnostic criteria comprising the administration of edaravone is rendered obvious in view of the cited prior art teachings.
Thus, the cited claims of the instant application are rendered obvious over the cited claims of ‘310 and thus not patentably distinct.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-20 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Yoshino et al. U.S. Publication No. 2008/0161378 A1 (same as EP-174960 of record) (herein referred to as Yoshino et al.); Yoshino et al. (2006, Amyotrophic Lateral Sclerosis, 2006, Volume 7, pages 247-251-of record) (herein referred to as Yoshino 2006); in view of Yoshino et al. (herein referred to as Yoshino 2003) (2003, Japanese Journal of Neurotherapy, Vol. 20 No. 5, pages 557-584-Provided on IDS dated June 2, 2014-English Translation of record); Traynor et al. (Arch. Neurol. 2000, 57, pages 1171-1176-of record) and Cedarbaum et al. (1999, Journal of the Neurological Sciences, Vol. 169, pages 13-21 of record).
Claims 1-20 of the instant application claim a method for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis, comprising: administering an effective amount of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof in a range of 15 mg to 240 mg per dose to a patient in need thereof if the patient is in a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more, wherein the administering comprises administering the effective amount to the patient for a plurality of administration periods establishing an initial administration period, an initial drug holiday period, and a number of doses per day based on a condition or conditions of the patient, and repeating an administration period and a drug holiday period such that the patient undergoes at least three administration periods including the initial administration period such that the specific patient group scores 2.5 points or better than a placebo administration group with respect to ALSFRS-R when the plurality of administration periods is six administration periods establishing an initial 14-day administration period and an initial 14-day drug holiday period, and thereafter, repeating the administration period of 10 out of 14 days and the drug holiday period of 14 days. The cited claims also comprise evaluating the patient for efficacy of 3-methyl-1-phenyl-2-pyrazolin-5-one or a physiologically acceptable salt thereof based on ALSFRS-R and %FVC; and selecting the patient for treating amyotrophic lateral sclerosis or suppressing progress of amyotrophic lateral sclerosis with 3-methyl-1-phenyl-2-pyrazolin-S-one or a physiologically acceptable salt thereof if the patient is a specific patient group in which each patient scores two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more. The claims also claim the patient is determined to be probable ALS according to the revised El Escorial diagnostic criteria.
Yoshino et al. teaches a medicament for treating ALS or symptoms caused by ALS and/or suppressing the progression of ALS comprising the administration of a compound of formula (I) (abstract). A preferred compound of formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one [0028]. Yoshino et al. teaches that a particularly preferred example of a course of a drug administration period and a drug holiday period consists of an initial drug administration period of 14 days, and a drug holiday period of 14 days, followed by repetitions of the following combination periods: drug administration period of 5 days per week for 2 weeks, and drug holiday period of 14 days ([0109]-[0111]).
Yoshino et al. specifically teaches and claims a method of treating ALS or symptoms caused by ALS and/or suppressing the progression of ALS comprising the administration of 3-methyl-1-phenyl-2-pyrazoline-5-one wherein the administration consists of an initial drug administration period of 14 days and a drug holiday period of 14 days followed by repetitions of drug administration for 5 days per week for 2 weeks and a drug holiday period of 14 days ([0012]-[0014] and claims 1-7 and 17-23 on page 9).
Yoshino et al. teaches that the symptoms caused by ALS which are improved by treatment include decreased respiratory function, voice and speech disorders, dysphagia, and upper and lower extremity motor disorders ([0117] and claims 15, 16, 31 and 32). Yoshino et al. specifically teaches suppression of decrease in respiratory function in ALS [0118].
Yoshino et al. specifically exemplifies the treatment of ALS comprising the administration of edaravone wherein 30 mg or 60 mg of edaravone was intravenously administered once daily for 14 consecutive days (initial treatment period) followed by a 2 week drug holiday period (initial drug holiday period) and thereafter administration was carried out for 10 days out of 14 days (2nd treatment period) followed by a 2 week holiday period (2nd drug holiday period), and treatments similar to the 2nd administration period were repeated 4 times (the 3rd to 6th administration periods) ([0120] and [0121]). Yoshino et al. further teaches determining the ALSFRS-R score starting at 6 months prior to treatment, during treatment and after the end of treatment [0122]. Yoshino et al. teaches treating patients with an ALSFRS-R score of 38 just prior to treatment [0122]. Yoshino teaches that the suppression rate in patients treated with 30 mg edaravone was 20% and those treated with 60 mg edaravone was 50% which clearly indicate that the edaravone and the method for administering the edaravone exert effects of suppressing a decrease in the ALSFRS-R score which is a rating scale for ALS ([0133]-[0134]).
Yoshino et al. teaches that the term %FVC stands for the percent predicted forced vital capacity and is generally used as an index in a method for objectively evaluating respiratory function in ALS patients [0135]. Yoshino et al. further teaches measuring the %FVC prior to treatment, during treatment and after the end of treatment ([0135]-[0136]). Yoshino teaches that the rate of decrease of %FVC during 6 months in untreated ALS patients was 13.8% [0135]. The rate of decrease of %FVC during 6 months in treated (30 mg edaravone) ALS patients was 9.3% [0137]. The rate of decrease of %FVC during 6 months in treated (60 mg edaravone) ALS patients was 4.5% [0137]. Yoshino teaches that Radicut (edaravone) injection 30 mg significantly suppressed both the decrease of %FVC and the increase of PaCO2 in ALS patients, and the respiratory function was maintained [0140].
Thus Yoshino et al. specifically teaches evaluating an ALS patient based on ALSFRS-R and %FVC. Yoshino et al. further specifically teaches treating ALS comprising the administration of edaravone.
Yoshino 2006 teaches treating patients diagnosed with sporadic amyotrophic lateral sclerosis (SALS) or familial amyotrophic lateral sclerosis (FALS) with either 30 or 60 mg of edaravone injections every day for two weeks and then patients were observed for two weeks without edaravone treatment (page 248). The drug was then administered again for five days a week, for two weeks, followed by a two-week observation period without edaravone treatment and this treatment observation cycle was repeated five times for a total duration of six months (page 248). Yoshino 2006 teaches that the ALSFRS-R score was determined for six months prior to treatment and during treatment wherein the decline in the ALSFRS-R score was significantly less than that in the six months prior to edaravone administration (pages 248-249). Thus Yoshino 2006 teaches treating ALS and suppressing disease progression as well as treating symptoms of ALS comprising the administration of edaravone by an initial 14-day administration period and an initial 14-day drug holiday and then repeating an administration period for 10 out of 14 days and a 14-day drug holiday period.
Thus Yoshino 2006 specifically teaches evaluating an ALS patient based on ALSFRS-R. Yoshino 2006 further specifically teaches treating ALS comprising the administration of edaravone.
The Yoshino references do not specifically teach selecting a patient for treatment if the patient scores two or more points from all items constituting the ALSFRS-R in combination with %FVC of 80% or more. The Yoshino references do not specifically teach that the patients were diagnosed based on the revised El Escorial diagnostic criteria.
Yoshino 2003 teaches that a known marker for oxidative stress is 3NT which is mediated by peroxynitrite and is increased in the spinal cords of ALS patients (page 3). Yoshino 2003 teaches that oxidative stress caused by peroxynitrite is thought to play a great role in sporadic ALS and there are expectations for a therapeutic agent having the action of eliminating first and foremost peroxynitrite by protecting against damage to the motor neurons occurring in ALS (page 3). Yoshino 2003 teaches that edaravone is a free radical scavenger (page 3). Yoshino 2003 teaches treating ALS comprising the administration of edaravone (pages 2-3 of Translation). Yoshino 2003 teaches 3NT in the cerebrospinal fluid, which is the oxidative stress marker, significantly declined when edaravone was administered for 14 days (pages 9-10). Yoshino 2003 teaches administration of 30 mg/day of edaravone to patients for 14 days followed by 14 days wherein the drug was withheld (pages 12-13 of Translation). Yoshino 2003 further teaches that progress of ALS can be inhibited by repeated administration of a daily 30 mg dose of edaravone for 10 days (page 15 of Translation).
Yoshino 2003 further teaches that administration of edaravone at the initial phase of the disease when peroxynitrite is eliminated early would make it possible to expect greater clinical validity (page 17 of Translation). Yoshino 2003 teaches that Figure 2 demonstrates that groups having ALSFRS-R of 40 or more points which do not require intervention in daily life tend to have a smaller decline in the score 6 months later (page 17 of Translation).
Cedarbaum et al. teaches that the ALS functional rating scale (ALSFRS) is a validated questionnaire-based scale that measures physical function in carrying out activities of daily living of patients with ALS (page 13). Cedarbaum et al. teaches a revised ALSFRS which adds three evaluation items to replace the breathing scale of the ALSFRS (page 13 and Table 1 pages 14-15). Cedarbaum et al. teaches a score of 0-4 for each of the 12 categories and thus a maximum score would be 48 wherein the patient exhibits no symptoms of ALS.
Traynor et al. teaches that ALS is a progressive degeneration of upper and lower motor neurons and patients with findings suggestive of ALS are accorded different levels of diagnostic certainty (suspected, possible, probable and definite ALS) by application of a set of defined diagnostic criteria (page 1171). Traynor et al. teaches that the diagnostic criteria was established in 1991 as the El Escorial diagnostic criteria and was revised in 1997 as the Airlie House diagnostic criteria (page 1171).
Accordingly, at the time of the instant invention, the use of edaravone in the treatment of ALS was well-known in the art as taught by each of the three Yoshino references as described above. Based on the teachings of Yoshino 2003, it would have been obvious to a person of ordinary skill in the art that a patient in the earlier stages of ALS would have a better treatment outcome with edaravone therapy as compared to patients in the more advanced stages of the disease since Yoshino 2003 teaches that patients scoring 40 or more points on the ALSFRS-R and do not require intervention in daily life tend to have a smaller decline in the score 6 months following treatment with edaravone. A patient who scores two or more points from all items constituting the ALSFRS-R in combination with %FVC of 80% or more as claimed, is clearly a patient in the earlier stages of the disease and consistent with the patient as taught in Yoshino 2003 that scores 40 or more points on the ALSFRS-R and do not require intervention in daily life since Cedarbaum et al. teaches that scores of less than 2 would require intervention in daily life and would be consistent with a patient in the advanced states of the disease. For example, a person with a score of 1 in category 6 would need an attendant for self-care, if a person scores a 1 in category 9 they would need assistance with climbing stairs, etc. Thus a person of ordinary skill in the art would have been motivated to treat patients in the earlier stages of ALS including a patient as claimed who scores two or more points from all items of the ALSFRS-R in combination with %FVC of 80% or more, according to the teachings of Yoshino et al. with a reasonable expectation of improved results, in view of the teachings of Yoshino 2003 which teaches that groups scoring 40 or more points on the ALSFRS-R scale who do not require intervention in daily life tend to have a smaller decline in the score 6 months after treatment with edaravone. Therefore, selecting a patient who scores two or more points from each of all items constituting ALSFRS-R in combination with %FVC of 80% or more for treatment with edaravone is rendered obvious in view of the cited prior art teachings.
In other words, at the time of the instant invention, it would have been obvious to a person of ordinary skill in the art to treat patients according to the teachings of the Yoshino references wherein the patient has 40 or more points on the ALSFRS and do not require intervention in daily life since Yoshino 2003 teaches that said patients tend to have a smaller decline in the score 6 months following treatment with edaravone. Thus, the claims of the instant application are rendered obvious since a patient having a score of 40 or more or a patient that does not require intervention in daily life is necessarily a patient having a score of two or more points from all items of the ALSFRS-R since Cedarbaum et al. teaches that scores of less than 2 would require intervention in daily life. For example, a person with a score of 1 in category 6 would need an attendant for self-care, if a person scores a 1 in category 9 they would need assistance with climbing stairs, etc. Thus, treating a patient who scores two or more points from all items of the ALSFRS-R as claimed in the instant application is rendered obvious in view of the cited prior art teachings. Moreover, as taught by Cedarbaum et al. patients having a mean ALSFRS-R score of 38.0 points also have a mean %FVC of 87.5. Thus, it would have been obvious to a person of ordinary skill in the art that a patient with 40 or more points on the ALSFRS-R and not requiring intervention in daily life as taught by Yoshino 2003 would also have a %FVC of 80% or more as claimed in the instant application.
Therefore, since treating the claimed patient population comprising the same administration steps as claimed is rendered obvious, achieving the same effects as claimed are also rendered obvious. Thus, achieving a better ALSFRS-R score than untreated patients as well as achieving the same difference between an ALSFRS-R score before treatment and after treatment, and reducing the risk of death or tracheostomy greater than other patient populations as claimed in the instant claims are rendered obvious.
Although the cited references do not specifically teach that the patients were diagnosed based on the revised El Escorial diagnostic criteria, it would have been within the skill of an ordinary artisan to diagnose a patient with a particular disease based on techniques well-known in the art prior to treating said patient.
Accordingly, at the time of the instant invention, it would have been obvious to a person of ordinary skill in the art to diagnose patients with ALS based on techniques well-known in the art such as by the revised El Escorial (Airlie House) diagnostic criteria as taught by Traynor et al.. Thus, since the revised El Escorial (Airlie House) diagnostic criteria is a suitable method for diagnosing ALS at the time of the instant invention, it would have been obvious to a person of ordinary skill in the art to diagnose a patient suspected of having ALS by the revised El Escorial (Airlie House) diagnostic criteria with a reasonable expectation of success. Thus, treating a patient having ALS according to the methods of Yoshino et al. comprising the administration of edaravone, who is diagnosed by the revised El Escorial (Airlie House) diagnostic criteria is rendered obvious in view of the cited prior art teachings.
With respect to the limitation that the edaravone is administered in a range of 15 mg to 240 mg per dose to the patient, Yoshino et al. specifically exemplifies the treatment of ALS comprising the administration of edaravone wherein 30 mg or 60 mg of edaravone was administered for 14 consecutive days followed by a 2 week holiday period and thereafter administration was carried out for 10 days out of 14 days followed by a 2 week holiday period ([0120] and [0121]). Yoshino 2006 teaches treating patients diagnosed with sporadic amyotrophic lateral sclerosis (SALS) or familial amyotrophic lateral sclerosis (FALS) with either 30 or 60 mg of edaravone injections every day for two weeks and then patients were observed for two weeks without edaravone treatment (page 248). Yoshino 2003 teaches administration of 30 mg/day of edaravone to patients for 14 days followed by 14 days wherein the drug was withheld (pages 12-13 of Translation).
Thus, all of the Yoshino references specifically teach administration of edaravone within the claimed range. Thus, by following the teachings and suggestions of the prior art, one would necessarily administer edaravone at an optimal dosage within the range as claimed which will necessarily achieve the same effects as claimed.
Thus, the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 1-20 are rejected. No claims are allowed.
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 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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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM