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 .
It is to be noted that the last Office Action was based on the claims of the preliminary amendment filed on September 12, 2023. However, in their response filed on April 23, 2026, applicant correctly pointed out that the Office never entered the preliminary amendment of September 12, 2013 and thus argued that all 63 claims as originally filed on March 23, 2023 should have been examined. The Examiner agree with applicant’s such argument, and in this Office Action, all pending claims included in the claim amendment of April 23, 2026 (except for claims 14-16, 18-20, 34-37, 41-55 and 62 - see Paragraphs 11 and 12 below) were examined on the merit, and this Office Action is made non-final.
Applicant canceled claims 6, 17, 21 and 58 in the amendment of April 23, 2026.
Claim Objections
Claim 1 is objected to because of the following informalities: (i) on line 3, applicant need to change “subject comprising” to --- subject, comprising ---. (ii) on line 5, applicant need to either delete “between” or change “between about 1 year of age to about 12 years of age” to --- between about 1 year of age and about 12 years of age ---. Appropriate correction is required.
Claims 1 and 8-13 are objected to because of the following informalities: In claims 1 and 8, applicant recite “wherein the pediatric subject is administered . . . mitapivat or . . . a pharmaceutically acceptable salt of mitapivat . . .”. Such phrase sounds awkward because the medication is what is being administered, not the patient. Appropriate correction is required.
Claim 22 is objected to because of the following informalities: on line 4, applicant need to change “40 kg comprising” to --- 40 kg, comprising ---. Appropriate correction is required.
Claim 26 is objected to because of the following informalities: on line 4, applicant need to change “20 kg comprising” to --- 20 kg, comprising ---. Appropriate correction is required.
Claim 30 is objected to because of the following informalities: on line 4, applicant need to change “40 kg comprising” to --- 40 kg, comprising ---.. Appropriate correction is required.
Claim 38 is objected to because of the following informalities: on line 4, applicant need to change “20 kg comprising” to --- 20 kg, comprising ---.
Claim 63 is objected to because of the following informalities: (i) on line 1, applicant need to insert --- from --- between “selected” and “the group”. (ii) on line 2, applicant need to delete “from” Appropriate correction is required.
Claim 64 is objected to because of the following informalities: on line 2, applicant need to change “the list” to --- the group ---. Appropriate correction is required.
Claims 14, 16, 18-20, 34, 36, 37, 41-47, 49, 51, 53-55 and 62 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims 14, 16, 18-20, 34, 36, 37, 41-47, 49, 51, 53-55 and 62 have not been further treated on the merits.
Furthermore, it is to be noted that claims 15, 35, 48, 50 and 52 also have not been further treated on the merits (except for the 112(b) rejection shown in Paragraph 14 below): even though they are single dependent claims and thus are not improper multiple dependent claims, they depend from the improper dependent claims 14, 34, 47, 49 and 51, respectively, and thus their scopes cannot be determined (see Paragraph 14 below).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 15, 35, 48, 50 and 52 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
As stated above, instant claims 15, 35, 48, 50 and 52 depend from the improper dependent claims 14, 34, 47, 49 and 51, respectively, and thus scopes of claims 15, 35, 48, 50 and 52 cannot be determined, thus rendering these claims indefinite.
Claims 22-25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 22 recites “administering to the pediatric subject one or more granules . . ., wherein each granule comprises mitapivat hemisulfate sesquihydrate in an amount equivalent to about 1 mg of mitapivat, and wherein the amount of mitapivat administered to the pediatric subject is about 20 mg, about 10 mg, or about 2 mg.” Thus, according to claim 22, the minimum amount of mitapivat administered to the pediatric subject is about 2 mg. Since each granule comprises about 1 mg of mitapivat, it seems that at least two granules should be administered to the pediatric subject. Yet claim 22 recites that one or more granules are administered to the pediatric subject, thus causing confusion and indefiniteness. Didn’t applicant mean to say --- two or more granules --- ?
Claim 40 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.
Claim 40, which depends from claim 38 or 39, as currently written, is not consistent with both of the parent claims 38 and 39 for the following reasons, thus causing confusion and indefiniteness:
According to claim 38, an initial amount of mitapivat (or its salt) is administered for a first period of time. After the first period of time, the hemoglobin level is assessed, and if the hemoglobin level is not within the target level, a first adjusted amount of mitapivat (or its salt) is administered (and it is implied that the first adjusted amount is administered for a second period of time although the claim does not state it).
According to claim 39, the first adjusted amount of mitapivat (or its salt) is administered for a second period of time. After the second period of time, the hemoglobin level is assessed, and if the hemoglobin level is not within the target level, a second adjusted amount of mitapivat (or its salt) is administered (and it is implied that the second adjusted amount is administered for a third period of time although the claim does not state it).
Yet, claim 40 recites that “the method further comprises administering a third adjusted amount of mitapivat . . . for a third period of time if the pediatric subject’s hemoglobin level is not within the target hemoglobin level after the second period of time; or continuing to administer the second adjust amount if the pediatric subject’s hemoglobin level is within the target hemoglobin level.”.
For the case where claim 40 depends from claim 38, in order to be consistent with the parent claim 38, applicant will have to make the following changes: (i) since there is insufficient antecedent basis for the limitations "after the second period of time" and “the second adjusted amount” in lines 4-5 of claim 40, applicant will have to insert --- for a second period of time --- on the 2nd line from the bottom of instant claim 38 (between “water” and “if”) and change “the second adjusted amount” in lines 4-5 of claim 40 to --- the first adjusted amount ---, and (ii) change “a third adjusted amount “ on line 2 of claim 40 to --- a second adjusted amount ---.
For the case where claim 40 depends from claim 39, in order to be consistent with the parent claim 39, applicant will have to make the following changes: (i) the phrase “for a third period of time” (in line 3 of claim 40) will have to be changed to --- for a fourth period of time ---; (ii) “after the second period time” (in line 4 of claim 40) will have to be changed to --- after the third period time ---; and (iii) applicant will also have to insert --- for a third period of time --- on the 2nd line from the bottom of instant claim 39 (between “water,” and “if”).
Therefore, it can be seen that when claim 40 depends from claim 38 or claim 39, two mutually exclusive changes will have to be made on a single claim (claim 40). Thus, in order to overcome instant 112(b) rejection on claim 40, the Examiner would like to suggest applicant to (i) make instant claim 40 depend from claim 39 ONLY and (ii) make necessary changes (as suggested above by the Examiner) in claim 40 so as to be consistent with the parent claim 39.
Claim 63 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.
Claim 63 recites a step of administering to the pediatric subject an initial amount of mitapivat or its salt for a first period of time and later recites a step of assessing the body weight of the pediatric subject over a period of time. It is unclear to the Examiner what applicant mean by “over a period of time”. Do applicant mean assessing the body weight of the pediatric subject over the first period of time, over any period of time after the first period of time, or any period of time? Appropriate correction and/or clarification is necessary.
Claim Rejections - 35 USC § 103
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-5, 7-13, 22-33, 56, 57, 59-61 and 64 are rejected under 35 U.S.C. 103 as being unpatentable over Sizemore et al (WO 2019/104134 A1) in view of CDC chart (“2 to 20 years: Boys Stature-for-age and Weight-for-age percentiles” – a chart published on May 30, 2000 and obtained from the website: https://www.cdc.gov/growthcharts/data/set2clinical/cj41c071.pdf ), Agresta et al (WO 2016/201227 A1) and Lee et al (“Sprinkle formulations-A review of commercially available products”, Asian Journal of Pharmaceutical Sciences, vol.15(3) (July 2019), pg.1-19) (with a Wikipedia article on “Capsule (pharmacy)” obtained from the website: https://en.wikipedia.org/wiki/Capsule_(pharmacy) , which is cited here merely to support the Examiner’s assertion that Size 1 Capsule has a volume of 0.48 mL, a length of 19.4 mm and a diameter of 6.91 mm).
Sizemore teaches (abstract, [0042], [0056]-[0059], [0125] and [0127]) a method of treating a disease selected from pyruvate kinase deficiency, sickle cell disease or thalassemia, which comprises administering to a subject in need thereof an effective amount of crystalline Form A. Crystalline Form A refers to a hemisulfate sesquihydrate of Compound 1, and Compound 1 is N-(4-(4-(cyclopropylmethyl)piperazine-l- carbonyl)phenyl)quinoline-8-sulfonamide, which structure is shown below:
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. Thus, Sizemore’s Compound 1 is instant mitapivat (se [0003] of present specification), and Sizemore’s Crystalline Form A, which is a hemisulfate sesquihydrate of Compound 1 is mitapivat hemisulfate sesquihydrate (instant pharmaceutically acceptable salt of mitapivat). Sizemore further teaches ([0053]) that the subject in need of the treatment can refer to a human child no more than 18 years old. Thus, it would have been obvious to one skilled in the art to administer an effective amount of Sizemore’s Crystalline Form A to a human child of 18 years old or less with a reasonable expectation of treating pyruvate kinase deficiency, sickle cell disease or thalassemia. Such range for the age overlaps with instant ranges for the age of the pediatric subject of claim 1 (about 1 to 12 years of age); claims 2, 7 and 10 (about 2 years of age to less than about 12 years of age); claims 3 and 12 (about 1 year of age to less than about 2 years of age), thus rendering instant age rages prima facie obvious. In the case “where the [claimed] ranges overlap or lie inside ranges disclosed by the prior art,” a prima facie case of obviousness would exist which may be overcome by a showing of unexpected results, In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).
With respect to instant range for the body weight of the pediatric subject, although Sizemore does not explicitly teach such limitation, CDC chart (“2 to 20 years: Boys Stature-for-age and Weight-for-age percentiles” – a chart published on May 30, 2000 and obtained from the website: https://www.cdc.gov/growthcharts/data/set2clinical/cj41c071.pdf ) indicates that 50 percentile weight for boys aged 18 years old or less is 67 kg or less. Such weight range indicated by CDC overlaps with instant ranges for the weight of the pediatric subject of claim 1 (about 7 kg to less than about 40 kg), claim 4 (about 7 kg to less than about 20 kg), claims 5 and 7 (about 20 kg to less than about 40 kg), claim 10 (about 7 kg to less than about 20 kg) and claim 22 (about 20kg to less than about 40kg), thus rendering instant weight ranges prima facie obvious. In re Wertheim, supra.
With respect to instant limitation of administering mitapivat or its salt together with food or water, although Sizemore does not explicitly teach such limitation, first of all, Agresta teaches (pg.40, lines 6-7) that food has a minimal effect on the exposure to Compound 1 (instant mitapivat – see pg.4, lines 1-4), which means that it is safe to take mitapivat together with food. Secondly, as evidenced by Lee et al (see both paragraphs under Introduction on pg.1; pg.2, left-hand column, 1st paragraph), it is known in the art that even though dosage forms like capsules and tablets are preferred due to dosing convenience, high physicochemical stability and cost-effectiveness, the large size of solid formulations is challenging for patients with dysphagia (often the elderly and children) to swallow, which in turn promoted the development of sprinkle formulations. Sprinkle formulations are drug containing pellets or granules that can be mixed with soft food before administration. These formulations provide almost the same dosing flexibility and ease of ingestion as liquid formulations when sprinkled on liquid or semi-solid vehicles, such as apple sauce, pudding or yogurt. The food taken together with the drug can also mask the unpleasant taste and smell of the drug substance which potentially improves patient compliance. Since Sizemore teaches ([0219]) that its Crystalline Form A (instant mitapivat hemisulfate sesquihydrate) can be formed into a tablet either through dry or wet granulation, it would have been obvious to one skilled in the art to use Sizemore’s Crystalline Form A in granular form (instead of tablet form) so as to be able to sprinkle it on food (such as apple sauce or yogurt – as listed in instant claim 64) before administering to a human child (under age of 18) with a reasonable expectation of making Crystalline Form A easier to swallow for children (who usually have dysphagia) and masking any unpleasant taste and smell of Crystalline Form A so as to improve patience compliance.
With respect to instant limitation “wherein the pediatric subject is administered from about 0.5 mg to about 25 mg of mitapivat or an amount of a . . . salt of mitapivat that is equivalent to an amount of about 0.5 mg to about 25 mg of mitapivat”, Sizemore teaches ([00111]) that a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgement of treating physicians and severity of the particular disease. Sizemore further teaches ([00112]) that Crystalline Form A (mitapivat hemisulfate sesquihydrate – instant pharmaceutically acceptable salt of mitapivat) is formulated for administration at a dose equivalent of about 2 mg to about 3000 mg of Compound 1 (instant mitapivat). Under such general guideline given by Sizemore, instant range (about 0.5 – 25 mg) of claim 1 (as well as instant ranges of claims 8-13) for the dosage amount of mitapivat or the dosage amount for its salt equivalent to the dosage amount of mitapivat would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 233.
With respect to instant limitation “wherein the mitapivat or a pharmaceutically acceptable salt thereof is administered once or twice daily”, Sizemore teaches ([00112]) that the dosing may be administered once, twice or three times daily.
Thus, Sizemore in view of CDC chart, Agresta and Lee renders obvious instant claims 1-5, 7-13 and 64.
With respect to instant claims 22-25, for the reasons already explained above, Sizemore in view of CDC chart, Agresta and lee teaches or renders obvious administering to a pediatric subject of about 2 years of age to less than about 12 years of age and having a body weight of about 20 kg to less than about 40 kg one or more granules containing instant mitapivat hemisulfate sesquihydrate together with food or water once or twice daily (the Examiner established above that it would have been obvious to one skilled in the art to use Sizemore’s Crystalline Form A in granular form and sprinkle it on food before administering to a human child (under age of 18)). As to instant limitation of each granule comprising mitapivat hemisulfate sesquihydrate in an amount equivalent to about 1 mg of mitapivat, first of all, Sizemore teaches ([00114]) that its tablet formulation contains Crystalline Form A (mitapivat hemisulfate sesquihydrate) in an amount equivalent to about 1 to 200 mg of Compound 1 (mitapivat). This means that the total amount of mitapivat for all of the granules in each tablet ranges from 1 to 200 mg. Secondly, Lee teaches (pg.14, 1st paragraph under section 2.4) that granules range in size from 0.85 mm to 4.75 mm. Thirdly, the Examiner estimates that a typical tablet would be close in size to Size 1 Capsule, which has a volume of 0.48 mL, a length of 19.4 mm and a diameter of 6.91 mm (as evidenced by Wikipedia article on “Capsule (pharmacy)” obtained from the website: https://en.wikipedia.org/wiki/Capsule_(pharmacy) – see the table on pg.3). As calculated by the Examiner, assuming that granules are spherical, a 0.85 mm granule would have a volume of 0.0003216 mL, and 4.75 mm granule would have a volume of 0.0561 ml. This means that for a tablet that is the size of Size 1 Capsule, there are about 1492 granules (0.48 mL divided by 0.0003216 mL = 1492) of size 0.85 mm in a tablet; and there are about 9 granules (0.48 mL divided by 0.0561 mL = 8.55) of size 4.75 mm in a tablet. Since Sizemore teaches that a tablet can contain from 1 to 200 mg of mitapivat equivalent, this means that the mitapivat equivalent for each granule ranges from 1/1492 mg to 200/9 mg, which is 6.7 x 10-4 mg to 22.2 mg of mitapivat equivalent for each granule. Instant range “about 1 mg” of mitapivat equivalent for each granule would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Alternatively, the range 6.7 x 10-4 mg to 22.2 mg for the mitapivat equivalent for each granule overlaps with instant range about 1 mg, thus rendering instant range prima facie obvious. In re Wertheim, supra. As to instant limitation as to the (total) amount of mitapivat administered to the pediatric subject being about 20 mg, about 10 mg, or about 2mg, as discussed above, Sizemore teaches that Crystalline Form A (instant mitapivat hemisulfate sesquihydrate) is formulated for administration at a dose equivalent of about 2 mg to about 3000 mg of Compound 1 (instant mitapivat). Instant ranges about 20 mg, about 10 mg or about 2mg would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Alternatively, Sizemore’s range about 2 mg to about 3000 mg overlaps with instant ranges about 20 mg, about 10 mg or about 2mg, thus rendering instant ranges prima facie obvious. In re Wertheim, supra. Thus, Sizemore in view of CDC chart, Agresta and Lee renders obvious instant claims 22-25.
With respect to instant claims 26-29, for the reasons already explained above, Sizemore in view of CDC chart, Agresta and lee teaches or renders obvious administering to a pediatric subject of about 2 years of age to less than about 12 years of age and having a body weight of less than about 20 kg one or more granules containing instant mitapivat hemisulfate sesquihydrate together with food or water once or twice daily. Also, the Examiner already established above that the mitapivat equivalent for each granule ranges from 6.7 x 10-4 mg to 22.2 mg. Instant range “about 1 mg” of mitapivat equivalent for each granule would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Alternatively, the range 6.7 x 10-4 mg to 22.2 mg for the mitapivat equivalent for each granule overlaps with instant range about 1 mg, thus rendering instant range prima facie obvious. In re Wertheim, supra. As to instant limitation as to the (total) amount of mitapivat administered to the pediatric subject being about 10 mg, about 5 mg, or about 1mg, as discussed above, Sizemore teaches that Crystalline Form A (instant mitapivat hemisulfate sesquihydrate) is formulated for administration at a dose equivalent of about 2 mg to about 3000 mg of Compound 1 (instant mitapivat). Instant ranges about 10 mg, about 5 mg or about 1 mg would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Alternatively, Sizemore’s range about 2 mg to about 3000 mg overlaps with instant ranges about 10 mg, about 5 mg or about 1 mg, thus rendering instant ranges prima facie obvious. In re Wertheim, supra. Thus, Sizemore in view of CDC chart, Agresta and Lee renders obvious instant claims 26-29.
With respect to instant claims 30-33, for the reasons already explained above, Sizemore in view of CDC chart, Agresta and Lee teaches or renders obvious administering to a pediatric subject of about 1 year of age to less than about 2 years of age and having a body weight of about 7 kg to less than about 20 kg one or more granules containing instant mitapivat hemisulfate sesquihydrate together with food or water once or twice daily. Also, the Examiner already established above that the mitapivat equivalent for each granule ranges from 6.7 x 10-4 mg to 22.2 mg. Instant range “about 1 mg” of mitapivat equivalent for each granule would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Alternatively, the range 6.7 x 10-4 mg to 22.2 mg for the mitapivat equivalent for each granule overlaps with instant range about 1 mg, thus rendering instant range prima facie obvious. In re Wertheim, supra. As to instant limitation as to the (total) amount of mitapivat administered to the pediatric subject being about 10 mg, about 4 mg, or about 1mg, as discussed above, Sizemore teaches that Crystalline Form A (instant mitapivat hemisulfate sesquihydrate) is formulated for administration at a dose equivalent of about 2 mg to about 3000 mg of Compound 1 (instant mitapivat). Instant ranges about 10 mg, about 4 mg or about 1 mg would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Alternatively, Sizemore’s range about 2 mg to about 3000 mg overlaps with instant ranges about 10 mg, about 4 mg or about 1 mg, thus rendering instant ranges prima facie obvious. In re Wertheim, supra. Thus, Sizemore in view of CDC chart, Agresta and Lee renders obvious instant claims 30-33.
With respect to instant claims 56-57, the Examiner established above that it would have been obvious to one skilled in the art to use Sizemore’s Crystalline Form A in granular form and sprinkle it on food before administering to a human child. Such granules teach instant minitablet of claim 56. With respect to instant limitation as to each minitablet (granule) comprising about 0.1 mg to about 5 mg of mitapivat equivalent, the Examiner already established above that there is 6.7 x 10-4 mg to 22.2 mg of mitapivat equivalent for each granule (instant minitablet). Instant range about 0.1 mg to about 5 mg would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Alternatively, the range 6.7 x 10-4 mg to 22.2 mg for the mitapivat equivalent for each granule (minitablet) overlaps with instant range about 0.1 mg to about 5 mg, thus rendering instant range prima facie obvious. In re Wertheim, supra. As to instant range for the longest dimension or diameter being a length of about 10.0 mm to about 0.1 mm, as already discussed above, Lee teaches (pg.14, 1st paragraph under section 2.4) that granules range in size from 0.85 mm to 4.75 mm. Such range falls within instant range of about 0.1 mm to about 10.0mm, and thus teaches instant range. The limitation “wherein the minitablet is suitable for mixing with food before oral administration once or twice daily to patients with difficulties swallowing” (i.e., patients with dysphagia (often the elderly and children)) was already addressed above. Also, the subject matter of claim 57 was already discussed above in relation to instant claim 1. Thus, Sizemore in view of CDC chart, Agresta and Lee renders obvious instant claims 56 and 57.
With respect to instant claims 59-61, the Examiner established above that it would have been obvious to one skilled in the art to use Sizemore’s Crystalline Form A in granular form and sprinkle it on food before administering to a human child. Such granules teach instant minitablet of claim 59. With respect to instant limitation as to each minitablet (granule) comprising about 0.1 mg to about 5 mg of mitapivat equivalent, the Examiner already established above that there is 6.7 x 10-4 mg to 22.2 mg of mitapivat equivalent for each granule (instant minitablet). Instant range about 0.1 mg to about 5 mg would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Alternatively, the range 6.7 x 10-4 mg to 22.2 mg for the mitapivat equivalent for each granule (minitablet) overlaps with instant range about 0.1 mg to about 5 mg, thus rendering instant range prima facie obvious. In re Wertheim, supra. As to instant range for the longest dimension or diameter being a length of about 10.0 mm to about 0.1 mm, as already discussed above, Lee teaches (pg.14, 1st paragraph under section 2.4) that granules range in size from 0.85 mm to 4.75 mm. Such range falls within instant range of about 0.1 mm to about 10.0mm, and thus teaches instant range. The limitation “patients that are between about 1 year to about 12 years of age and weighing between about 7g to less than about 40 kg or adult patients with difficulties swallowing” was already addressed above. Also, the subject matter of instant claim 60 was already discussed above. Thus, Sizemore in view of CDC chart, Agresta and Lee renders obvious instant claims 59 and 60. With respect to instant claim 61, the Examiner already established above that there is 6.7 x 10-4 mg to 22.2 mg of mitapivat equivalent for each granule (instant minitablet). Instant range about 1 mg would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Alternatively, the range 6.7 x 10-4 mg to 22.2 mg for the mitapivat equivalent for each granule (minitablet) overlaps with instant range about 1 mg, thus rendering instant range prima facie obvious. In re Wertheim, supra. Thus, Sizemore in view of CDC chart, Agresta and Lee renders obvious instant claim 61.
Claim(s) 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over Sizemore et al (WO 2019/104134 A1) in view of CDC chart (“2 to 20 years: Boys Stature-for-age and Weight-for-age percentiles” – a chart published on May 30, 2000 and obtained from the website: https://www.cdc.gov/growthcharts/data/set2clinical/cj41c071.pdf ), Agresta et al (WO 2016/201227 A1), Lee et al (“Sprinkle formulations-A review of commercially available products”, Asian Journal of Pharmaceutical Sciences, vol.15(3) (July 2019), pg.1-19) and Grace et al (“Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency”, The NEW ENGLAND JOURNAL of MEDICINE, vol.381 (September 4, 2019), pg.933-944).
For the reasons already explained above, Sizemore in view of CDC, Agresta and Lee teaches or renders obvious instant claims 38-40, except for adjusting the dose of mitapivat or its salt depending on patient’s hemoglobin level measured after a given period of time following the administration of the drug. Grace reports (see abstract – see under METHODS) a study on the safety and efficacy of mitapivat in adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period. Grace teaches (pg.934, right-hand column, last paragraph and pg.935, left-hand column, first paragraph) that changes in doses during the core period were allowed on the basis of safety, side effect profile and hemoglobin level. Increases in doses were allowed if the hemoglobin level remained below the lower limit of the normal range. Dose decreases were allowed for adverse events thought to be related to mitapivat or if the hemoglobin level exceeded the midpoint of the normal range. It would have been obvious to employ Grace’ teaching in Sizemore’s method of treating a disease selected from pyruvate kinase deficiency (as modified by the teachings of CDC chart, Agresta and Lee) to adjust the amount of mitapivat or its salt according to the hemoglobin level assessed after a given period of time following the administration of the drug and continue to assess the hemoglobin levels and re-adjust the amount if the pediatric subject’s hemoglobin level is not within the target hemoglobin level or continue to administer the drug to the pediatric subject without further adjustment if the hemoglobin level is within the target hemoglobin level. Thus, Sizemore in view of CDC chart, Agresta, Lee and Grace renders obvious instant claims 38-40.
Claim(s) 63 is rejected under 35 U.S.C. 103 as being unpatentable over Sizemore et al (WO 2019/104134 A1) in view of CDC chart (“2 to 20 years: Boys Stature-for-age and Weight-for-age percentiles” – a chart published on May 30, 2000 and obtained from the website: https://www.cdc.gov/growthcharts/data/set2clinical/cj41c071.pdf ).
For the reasons already explained above, Sizemore in view of CDC chart teaches a method of treating pyruvate kinase deficiency, sickle cell disease and thalassemia in a human child of 18 years old or less (whose 50 percentile weight is 67 kg or less) by administering to the subject an effective amount of mitapivat hemisulfate sesquihydrate (i.e., a does equivalent of mitapivat which ranges from about 2 mg to 3000 mg) once or twice daily. Sizemore furthermore teaches ([00111]) a specific dosage (and treatment regimen) for any particular subject will depend upon a variety of factors including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgement of treating physicians and severity of the particular disease). Under such general guidelines given by Sizemore, determining optimum initial administration amount (such as about 0.5-25 mg or 05-15 mg) for the mitapivat or its salt based on the age and body weight of a human child of 18 years old or less (including a pediatric subject of about 1 year of age to about 12 year of age whose 50 percentile weight is 40 kg or less as shown in the CDC chart – the Examiner also notes that 50 percentile weight for 6k) would be within a realm of one of ordinary skill in the art. One skilled in the art would also find it obvious and natural to change the does as the pediatric subject grows older and gains body weight or continue administering the same initial dose if the pediatric subject’s body weight remains substantially the same.
Response to Arguments
Although applicant made a lengthy argument, the gist of the argument is as follows:
(I) Applicant first argue that the Examiner has not explained why one skilled in the art armed with the teachings of the cited prior arts would have specifically arrived at, (1) treating a condition selected from pyruvate kinase deficiency, sickle cell disease, and thalassemia; (2) in a pediatric subject; (3) with about 0.5 mg to about 25 mg of mitapivat or a pharmaceutically acceptable salt that is equivalent to an amount of about 0.5 mg to about 25 mg of mitapivat thereof together with food or water; (4) wherein the pediatric subject is between about 1 year of age to about 12 years of age; (5) has a body weight of about 7 kg to less than about 40 kg; and (6) wherein the mitapivat or a pharmaceutically acceptable salt thereof is administered once or twice daily. Applicant argue that the minimum requirement established by at least In Re Stepan Company and Ex Parte Sturgis has not been met and therefore, a prima facie case has not been met.
The Examiner disagrees. As already discussed above, Sizemore clearly teaches a method of treating a disease selected from pyruvate kinase deficiency, sickle cell disease or thalassemia, which comprises administering to a subject in need thereof an effective amount of Crystalline Form A, which is instant mitapivat hemisulfate sesquihydrate. Sizemore also clearly teaches ([0053]) that the term “subject” can refer to a human child no more than 18 years old. Thus, it would have been obvious to one skilled in the art to administer an effective amount of Sizemore’s Crystalline Form A (mitapivat hemisulfate sesquihydrate) to a human child of 18 years old or less with a reasonable expectation of treating pyruvate kinase deficiency, sickle cell disease or thalassemia. Such age range overlaps with instant age range (about 1 to 12 years of age) for the pediatric subject, thus rendering instant age rages prima facie obvious. In re Wertheim, supra. As to the body weight of the pediatric subject, the Examiner already explained above that although Sizemore does not explicitly teach such limitation, CDC chart clearly indicates that 50 percentile weight for boys aged 18 years old or less is 67 kg or less and that such weight range overlaps with instant weight range (about 7 kg to less than about 40 kg) for the pediatric subject, thus rendering instant weight ranges prima facie obvious. In re Wertheim, supra. Sizemore clearly teaches ([00112]) that the dosing may be administered once or twice daily. As to “about 0.5 mg to about 25 mg of mitapivat or a pharmaceutically acceptable salt that is equivalent to an amount of about 0.5 mg to about 25 mg of mitapivat thereof together with food or water”, after teaching ([00111]) that a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgement of treating physicians and severity of the particular disease, Sizemore gives a general teaching ([00112]) that Crystalline Form A (mitapivat hemisulfate sesquihydrate) is formulated for administration at a dose equivalent of about 2 mg to about 3000 mg of Compound 1 (instant mitapivat) (Sizemore also gives examples of narrower ranges for the dose equivalent of Compound 1 in the same paragraph). Under such general guidelines given by Sizemore, instant range (about 0.5 – 25 mg) for the dosage amount of mitapivat or the dosage amount for its salt equivalent to the dosage amount of mitapivat would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Lastly, the Examiner also established above that the cited prior arts teach or renders obvious instant limitation of administering mitapivat or its salt together with food or water. That is, as already discussed above, although Sizemore does not explicitly teach such limitation, first of all, Agresta teaches that food has a minimal effect on the exposure to Compound 1 (instant mitapivat), which means that it is safe to take mitapivat together with food. Secondly, as evidenced by Lee et al, it is known in the art that even though dosage forms like capsules and tablets are preferred due to dosing convenience, high physicochemical stability and cost-effectiveness, the large size of solid formulations is challenging for patients with dysphagia (often the elderly and children) to swallow, which in turn promoted the development of sprinkle formulations, which are drug containing pellets or granules that can be mixed with soft food before administration. These formulations provide almost the same dosing flexibility and ease of ingestion as liquid formulations when sprinkled on liquid or semi-solid vehicles (such as apple sauce, pudding or yogurt). The food taken together with the drug can also mask the unpleasant taste and smell of the drug substance which potentially improves patient compliance. Since Sizemore teaches ([0219]) that its Crystalline Form A (instant mitapivat hemisulfate sesquihydrate) can be formed into a tablet either through dry or wet granulation, it would have been obvious to one skilled in the art to use Sizemore’s Crystalline Form A in granular form (instead of tablet form) so as to be able to sprinkle it on food before administering to a human child (under age of 18) with a reasonable expectation of making Crystalline Form A easier to swallow for children (who usually have dysphagia) and masking any unpleasant taste and smell of Crystalline Form A so as to improve patience compliance. Thus, the Examiner believes she has sufficiently explained why one skilled in the art armed with the teachings of the cited prior arts would have specifically arrived at, (1) treating a condition selected from pyruvate kinase deficiency, sickle cell disease, and thalassemia; (2) in a pediatric subject; (3) with about 0.5 mg to about 25 mg of mitapivat or a pharmaceutically acceptable salt that is equivalent to an amount of about 0.5 mg to about 25 mg of mitapivat thereof together with food or water; (4) wherein the pediatric subject is between about 1 year of age to about 12 years of age; (5) has a body weight of about 7 kg to less than about 40 kg; and (6) wherein the mitapivat or a pharmaceutically acceptable salt thereof is administered once or twice daily.
(II) Applicant further argue that a proper obviousness analysis still requires a finding of a reasonable expectation of success. Applicant argue that obtaining pediatric dosages and administration form is by no means a straightforward or routine procedure and argue that one cannot simply optimize dosages from adults and obtain dosages that are appropriate, safe and efficacious for pediatric subjects. Applicant argue that there is a vast amount of variables and considerations, none of which are predictable, in order to arrive at a therapeutically safe and effective product, particularly for pediatric subjects. Applicant point out numerous differences between adult and child patients, such as biochemical differences (such as cytochrome P-450, gastric pH, intestinal mucosa, plasma protein binding), physical or biological differences (such as mouth anatomy), and compliance issues which are enhanced with children (such as bitter taste or pill size), and argue that there are a number of factors which must be considered and analyzed when preparing therapeutics for children, none of which are addressed or discussed in the prior arts cited. Applicant argue that the Office has given no rational for why one would be motivated to select the specific patient ages and weights, and the specific dosages amounts, among other variables and that the Office has not provided any evidence that doing so would lead to a reasonable expectation of success. Applicant conclude that taken together, all of the factors discussed above demonstrate that determining appropriate dosing levels of drugs for pediatric subjects, including Mitapivat, is not only a difficult and challenging task, but also unpredictable. Applicant argue that in light of their two clinical studies as shown in Exhibit B, which use the claimed doses and administration forms, they have provided evidence that proves that the claimed doses and administration forms have the ability to treat PKD (or have clinically meaningful effects on this disease) as claimed and argue that this would not be expected based on the prior arts cited by the Examiner.
Applicant’s arguments were carefully considered but were found to be unpersuasive. First of all, as addressed above, Sizemore already teaches that its drug (mitapivat hemisulfate sesquihydrate) can be administered to a human child of 18 years old or less (whose 50 percentile weight is known to be 67 kg or less). Sizemore gives a general teaching ([00112]) that its Crystalline Form A (mitapivat hemisulfate sesquihydrate) is formulated for administration at a dose equivalent of about 2 mg to about 3000 mg of Compound 1 (instant mitapivat) (Sizemore also gives examples of narrower ranges for the dose equivalent of Compound 1 in the same paragraph). Sizemore clearly teaches that a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgement of treating physicians and severity of the particular disease. Under all the general guidelines given by Sizemore and also under the teachings of Agresta and Lee, the Examiner still believes that instant pediatric dosage and administration form (sprinkle formulation (granules) to be taken with food or water) would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, supra. Furthermore, although applicant argue unpredictability in determining pediatric dosage for drugs (including mitapivat), it is the Examiner’s position that there are ways that are well known in the art to overcome such unpredictability. For example, Verscheijden et al (“Physiologically-based pharmacokinetic models for children: Starting to reach maturation?”, Pharmacology & Therapeutics, vol.211 (2020), 107541, pg.1-14), after first recognizing (see abstract) that developmental changes in children can affect the disposition and clinical effects of a drug, indicating that scaling an adult dose simply down per linear weight can potentially lead to overdosing, especially in very young children, teaches (abstract) that Physiologically-based pharmacokinetic (PBPK) models are compartmental, mathematical models that can be used to predict plasma drug concentrations in pediatric populations and acquire insight into the influence of age-dependent physiological differences on drug disposition. Verscheijden teaches (pg.3, left-hand column, 2nd paragraph) that pediatric PBPK modeling has developed from “proof of principle” to a valuable tool for the prediction of pharmacokinetics in children. Verscheijden teaches (pg.10, right-hand column, 1st paragraph) that, for example, PBPK models have been used to set a starting dose in a clinical trial with eribulin in children and adolescents 6-18 years of age or to inform deflazacort dose adjustments needed when given together with drugs that may cause interactions in children and adolescents 4-16 years of age. As evidenced by another review article, Zhou et al (“Predicting the correct dose in children: Role of computational Pediatric Physiological-based pharmacokinetics modeling tools” (CPT Pharmacokinetics Syst Pharmacol. Vol.12(1) (January 2023), pg.13-26), (see pg.13, right-hand column and pg.14, left-hand column, 1st paragraph), PBPK modeling is known as a type of pharmacokinetic (PK) prediction method that characterizes the concentration vs. time profile in the body, which is the foundation for determining whether a drug is therapeutic or harmful. In recent years, PBPK modeling has often been used to advise dosing in children. Between 2008 and 2016, 15% of PBPK modeling drug submissions to the US FDA contained pediatric simulations. Pediatric drug development was reported to be the second most common application of PBPK modeling in the FDA regulatory submissions. Zhou also teaches that PBPK modeling is utilized for various purposes in pediatric drug development, including initial pediatric dose selection. Therefore, the Examiner disagrees with applicant’s argument that determining appropriate dosing levels of drugs for pediatric subjects, including Mitapivat is unpredictable.
For the reasons stated above, instant 103 rejections over Sizemore in view of CDC chart, Agresta and Lee as well as instant 103 rejection on claim 63 over Sizemore in view of CDC chart still stand.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
July 10, 2026
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