DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 52-79 are pending. Claims 1-51 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/US2022/023703, filed on April 6, 2022. This application also claims priority to U.S. Provisional Patent Application No. 63/171,326 filed April 6, 2021; 63/255,153 filed October 13, 2021; and 63/288,978 filed December 13, 2021.
Specification - Abstract
The abstract of the disclosure is objected to because it is not in compliance with 37 C.F.R. 1.72 (b). Specifically, the sheet presenting the abstract includes other parts of the application or other material. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 60 and 61 are objected to because of the following informalities:
In claim 60:
“the treating comprises reducing propionic acid…” should read“the treating comprises reducing at least one metabolite selected from propionic acid…”
In claim 61:
“the treating comprises reducing 2-ketoisocaproate…” should read“the treating comprises reducing at least one metabolite selected from 2-ketoisocaproate…”
Appropriate correction is required.
Claims 54 and 55 are objected to under 37 CFR 1.75 as being a substantial duplicate of claim 53. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112(a) – Written description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 58 and 59 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification provides written description support for “an oral solution containing 8.4 or 59 mg/mL Compound 5 (equivalent to 10 or 70 mg/mL Compound 5A (sodium 2,2-dimethylbutanoate), respectively)” (para. 00193).
The specification does not provide written description support for an oral solution comprising 5 mg/mL to 75 mg/mL of sodium 2,2-dimethylbutanoate or comprising 10 mg/mL to 70 mg/mL of sodium 2,2-dimethylbutanoate.
Thus, claims 58 and 59 fail to comply with the written description requirement.
Claim Rejections - 35 USC § 112(a) - Enablement
Claims 74 and 76-79 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims methods of treating organic acidemias with 2,2-dimethylbutyric acid or pharmaceutically acceptable salt thereof.
State of the prior art
See the “Claim Rejections - 35 USC § 102” and “Claim Rejections - 35 USC § 103” sections below.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The presence or absence of working examples; amount of direction or guidance present; and quantity of experimentation necessary
The specification describes biochemical effects of administering 2,2-dimethylbutyric acid or its salts, such as reductions in metabolites associated with propionic acidemia or methylmalonic acidemia (see instant Examples 1-6). Such disclosures may be sufficient to enable methods of treating propionic acidemia or methylmalonic acidemia in a subject directed to lowering specific metabolite levels.
However, the presently claimed methods further require achieving a clinical outcome (i.e., improving a health-related quality of life score such as MetabQoL 1.0 score, PedsQL score, or Clinician-Reported Global Assessments of Severity and Change score or reducing frequency of metabolic decompensation events requiring an emergency room visit or hospitalization, etc.). These are patient-reported or clinician-assessed human clinical endpoints that are distinct from, and not inherently established by, the disclosed biochemical measurements from in vitro experimental studies that use primary hepatocytes isolated from the livers of patients with propionic acidemia or methylmalonic acidemia.
Accordingly, the instant specification does not provide a predictive correlation between the disclosed biochemical effects and the claimed patient-reported or clinician-assessed quality-of-life outcomes. Establishing such a relationship would require substantial clinical investigation to determine whether, and under what conditions, the observed biochemical changes translate into improvements in the recited quality-of-life metrics. In the absence of guidance demonstrating a reasonable expectation that these clinical outcomes would result from the disclosed treatment, undue experimentation would be required to practice the full scope of the claimed methods.
Claim Rejections - 35 USC § 112(a) – Scope of enablement
Claim 52 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method of treating propionic acidemia or methylmalonic acidemia in a subject in need thereof
does not reasonably provide enablement for:
A method of treating any organic acidemia in a subject in need thereof
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
See the “1. The nature of the invention” subsection within the “Claim Rejections - 35 USC § 112(a) – Enablement” section above.
State of the prior art
See the “Claim Rejections - 35 USC § 102” and “Claim Rejections - 35 USC § 103” sections below.
The level of the skill in the art
See the “1. The nature of the invention” subsection within the “Claim Rejections - 35 USC § 112(a) – Enablement” section above.
The presence or absence of working examples; amount of direction or guidance present; and quantity of experimentation necessary
While the instant application discloses experimental data that provide enablement support for a method of treating propionic acidemia and methylmalonic acidemia in a subject in need thereof, claim 52 is drawn more broadly to methods of treating any organic acidemia.
The working examples are limited to studies performed using primary hepatocytes isolated from the livers of patients with propionic acidemia or methylmalonic acidemia. The application does not provide experimental data, mechanistic explanation, or other technical guidance that the disclosed treatment would be effective for other types of organic acidemias (note: instant example 6 explicitly describes a proposed mechanism of action of 2,2-dimethylbutyric acid (or its sodium salt) in treating methylmalonic acidemia and propionic acidemia, not any organic acidemia).
Since the specification only provides support for treatment of specific subtypes of organic acidemia and does not teach how to make and use the invention across the full scope of the claim without undue experimentation, claim 52 is, thus, not fully enabled.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 52-79 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.
The term “about” in claims 52, 53, 56, 58, 59, 62-66, and 70-72 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification provides the following statement regarding numerical ranges:
“When a numerical range is disclosed herein, it is to be understood that all values and subranges therein are included as if each was expressly disclosed. For example, a range of from about 1 to about 100 is understood to include all values between 1 and 100, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, and 99 inclusive of all values and subranges therebetween. As an additional example, a range of from about 1 to about 100 is understood to include all subranges within the range, e.g., 1-42, 37-100, 25-65, 75-98, etc.” (para. 0021).
While this passage clarifies that values and subranges within a stated numerical range are included, the specification does not define the scope of values outside the stated endpoints that may fall within the range due to the use of the term “about.” The term “about” introduces some degree of variability beyond the expressly recited numerical limits, yet the specification provides no guidance as to the extent of deviation that is intended to be encompassed. Thus, claims 52, 53, 56, 58, 59, 62-66, and 70-72 are rendered vague and indefinite.
Claims 54, 55, 57, 60, 61, 67-69, and 73-79 which are dependent on claim 53, are also rejected for further requiring and/or reciting the indefinite limitation of claim 53.
Claims 54 and 55 recite the limitation "wherein the organic acidemia." Claims 54 and 55 are dependent on claim 53 which does not recite the general phrase, “an organic acidemia.” Thus, there is insufficient antecedent basis for this limitation in the claim.
Claims 62 and 63 recite the limitation “wherein the at least one metabolite…” Claims 62 and 63 are dependent on claims 60 and 61, respectively, which do not recite the general phrase “at least one metabolite.” Thus, there is insufficient antecedent basis for this limitation in the claim. See the “Claim Objections” section above to see how claims 60 and 61 can be modified to avoid a 112(b) issue.
Claims 70-72 recite the limitation “the total daily dose of sodium 2,2-dimethylbutanoate.” Claims 70-72 are dependent on claim 53 which does not recite a total daily dose of sodium 2,2-dimethylbutanoate. Thus, there is insufficient antecedent basis for this limitation in the claim.
To avoid a 112(b) issue for claims 70-72, the claims should read:
“The method of claim 53, wherein a total daily dose of sodium 2,2-dimethylbutanoate administered is…”
Claim 74 recites the limitation “a frequency of days in the hospital required for treatment/resolution of metabolic decompensations.” Claim 74 is dependent on claim 53 which does not recite a frequency of days in a hospital. Thus, there is insufficient antecedent basis for this limitation in the claim.
To avoid a 112(b) issue for claim 74, the claim should read:
“… a frequency of days in a hospital required for treatment/resolution of metabolic decompensations…”
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 54 and 55 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 54 recites “wherein the organic acidemia is propionic acidemia.” Claim 54 is dependent on claim 53 which already recites “A method of treating propionic acidemia… in a subject in need thereof…” Therefore, stating the organic acidemia is specifically propionic acidemia in claim 54 is redundant and claim 54 is not further limiting subject matter of the claim upon which it depends.
Claim 55 recites “wherein the organic acidemia is methylmalonic acidemia.” Claim 55 is dependent on claim 53 which already recites “A method of treating… methylmalonic acidemia in a subject in need thereof…” Therefore, stating the organic acidemia is specifically methylmalonic acidemia in claim 55 is redundant and claim 55 is not further limiting subject matter of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Note on 35 USC § 102 and § 103 Rejections
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 52-57 and 60-73 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Wamhoff et al. (Wamhoff) (WO2020186216A1; published September 17, 2020).
It is noted here that Examples 1-6 of the present application provide support for and partially enable the pending claim set.
Instant Examples 1-6 correspond to Examples 3, 5, 7, 8, 10, and 11 disclosed in Wamhoff which teach the same subject matter:
Instant Example 1 = Wamhoff Example 3:
Reduction of Propionyl-CoA Levels from All Sources Following Compound 5 (i.e., 2,2-dimethylbutanoic acid or sodium 2,2-dimethylbutanoate) Treatment in propionic acidemia (PA) primary Hepatocytes
Instant Example 2 = Wamhoff Example 5:
Reduction of Methylmalonyl-CoA and Propionyl-CoA Levels from All Sources Following Compound 5 Treatment of methylmalonic acidemia (MMA) Primary Hepatocytes
Instant Example 3 = Wamhoff Example 7
Effect on Ureagenesis Following Compound 5 Treatment
Instant Example 4 = Wamhoff Example 8
Reduction of isovaleryl-CoA in a Primary Hepatocyte Model of Isovaleric Acidemia Following Compound 5 Treatment
Instant Example 5 = Wamhoff Example 10:
Pharmacologic Activity of Compound 5 In Primary Hepatocytes from PA and MMA
Instant Example 6 = Wamhoff Example 11:
Proposed Mechanism of Action of Compound 5 in Treating MMA and PA
Wamhoff also discloses the following:
Regarding instant claims 52-56, 60-66, and 70-72:
Wamhoff “provides methods of treating metabolic disorders (e.g., organic acidemias) by reducing the formation of metabolites associated with such metabolic disorders” (para. 0074). “In some embodiments, at least one metabolite is reduced by least about 1% to about 100%” (para. 0013). “In some embodiments, the metabolite is propionic acid, 3- hydroxypropionic acid, 2-methylcitrate, methylmalonic acid, propionylglycine, or propionylcarnitine, or combinations thereof. In some embodiments, the at least one metabolite comprises 2-ketoisocaproate, isovaleryl-CoA, 3 -methylcrotonyl-CoA, 3-methylglutaconyl-CoA, 3 -OH-3-methylglutaryl-CoA, 2-keto-3-methylvalerate, 2-methylbutyryl-CoA, tiglyl-CoA, 2- methyl-3 -OH-butyryl-CoA, 2-methyl-acetoacetyl-CoA, 2-ketoisovalerate, isobutyryl-CoA, methylacrylyl-CoA, 3-OH-isobutyryl-CoA, 3-OH-isobutyrate, methylmalonic semialdehyde, propionyl-CoA, or methylmalonyl-CoA, or combinations thereof” (para. 0013).
Wamhoff also teaches the administration of about 30-50 mg/kg of 2,2-dimethylbutyric acid to treat one or more of the metabolic diseases disclosed herein (e.g., MMA, isovaleric acidemia [IVA], or PA) (para. 00112).
Wamhoff further teaches that “the amount of the compound disclosed herein, or a pharmaceutically acceptable solvate, ester, metabolite, or salt thereof, can be administered at about 0.001 mg/kg to about 100 mg/kg body weight” (para. 00153).
In some embodiments, the compound is 2,2-dimethylbutyric acid or sodium 2,2-dimethylbutyrate (para. 0095 and 00102)
“The compounds of the disclosure may be administered by any appropriate route of administration. As previously defined, the route includes, but is not limited to oral” (para. 00171).
“one or more compounds disclosed in Wamhoff may be administered one or more times a day, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day” (para. 00160).
Regarding instant claims 67-69:
Wamhoff also teaches that “In some embodiments, the patient treated accordance with the methods provided herein is a newborn, or is about 1 month to 12 months old, about 1 year to 10 years old, about 10 to 20 years old, about 12 to 18 years old, about 20 to 30 years old, about 30 to 40 years old, about 40 to 50 years old, about 50 to 60 years old, about 60 to 70 years old, about 70 to 80 years old, about 80 to 90 years old, about 90 to 100 years old, or any age in between” (para. 00161).
Regarding instant claim 57:
Sodium 2,2-dimethylbutyrate can be dissolved in water to form a solution (para. 00122) that can be orally administered (para. 00171).
Regarding instant claim 73:
In Wamhoff, Example 10, representative activity data for Compound 5 in primary hepatocytes (pHeps) from PA and MMA donors was demonstrated using the HemoShear REVEAL-Tx™ Technology. As a result, MCA levels were “dramatically reduced in both the PA and MMA donors, with an EC50 of 1.96 mM and 1.66 mM, respectively” (para. 00194, last sentence).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 58 and 59 are rejected under 35 U.S.C. 103 as being unpatentable over:
Wamhoff et al. (Wamhoff) (WO2020186216A1; published September 17, 2020)
Wamhoff teaches that sodium 2,2-dimethylbutyrate can be dissolved in water to form a solution (para. 00122) that can be orally administered (para. 00171). Wamhoff also teaches that “the amount of the compound disclosed herein, or a pharmaceutically acceptable solvate, ester, metabolite, or salt thereof, can be administered at about 0.001 mg/kg to about 100 mg/kg body weight” (para. 00153).
Wamhoff does not explicitly disclose an oral solution comprising 5 mg/mL to 75 mg/mL of sodium 2,2-dimethylbutyrate.
However, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to formulate an oral solution within this concentration range in order to deliver the therapeutically effective dosages of sodium 2,2-dimethylbutyrate taught by Wamhoff. Selecting a concentration suitable to achieve a known dosage through routine formulation adjustments would be considered obvious-to-try to a POSITA.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624