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 .
Claim Rejections - 35 USC § 112
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 9-13, 15-24 and 26-30 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 claims 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 inventors, at the time the application was filed, had possession of the claimed invention.
Claim 9 recites "A method for treating a mammal identified as (a) having a CDG and (b) having a biological sample containing an elevated level of one or more polyols, relative to the level of said one or more polyols in a biological sample from a control mammal not having said CDG […] and having a biological sample that does not contain an elevated level of said one or more polyols, relative to the level of said one or more polyols in said biological sample from said control mammal.” The terminology “An elevated level, relative to a level of said one or more polyols” contains very broad ranges, and while specific numbers and ranges (such as that the elevated level of the one or more polyols can be increased by at least 10% as compared to the level of the one or more polyols in the control biological sample. The method increased dose can be from about 0.5 mg/kg/day to about 5 mg/kg/day) are used in the specification (specifically as recited on page 5 of the instant specification, the instant claim uses broad terms for the definition for “elevated level”, and therefore does not clearly convey the claimed subject matter or show that the applicant had possession of this claimed limitation for any concentration of polyols.
In addition, claim 20 recites “determining that a measured level of at least one of said one or more polyols is elevated relative to a level of the one or more polyols in a biological sample from a control mammal that does not have said CDG […] biological sample that does not contain an elevated level of said one or more polyols, relative to the level of said one or more polyols in said biological sample from said control mammal.” The terminology “An elevated level, relative to a level of said one or more polyols” contains very broad range, and while specific numbers and ranges (such as that the elevated level of the one or more polyols can be increased by at least 10% as compared to the level of the one or more polyols in the control biological sample. The method increased dose can be from about 0.5 mg/kg/day to about 5 mg/kg/day) are used in the specification (specifically as recited on page 5 of the instant specification, the instant claim uses broad terms for the definition for “elevated level”, and therefore does not clearly convey the claimed subject matter or show that the applicant had possession of this claimed limitation for any concentration.
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 9-13, 15-24 and 26-30 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 “elevated level” in claims 9 and 20 is a relative term which renders the claim indefinite. The term “elevated level” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree to convey an elevated level, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The one or more polyols as recited in the instant claims are rendered indefinite by the use of this term.
The term “increased” in claims 9 and 20 is a relative term which renders the claim indefinite. The term “increased” is not defined by the claim, the specification does not provide a standard for ascertaining what the term “increased” means, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The ARI dosage as recited . It is unclear whether the terms “elevated level” and “increased” just has to be slightly more than the control value, or whether an “elevated level” of polyols it needs to be at least 10% as compared to a control sample, and whether an “increased” dose of said aldose reductase inhibitor (ARI) needs to be at least 50% greater than a dose previously administered to a mammal.
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.
Claim 9-12 and 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Perlstein et al (WO 2020040831 A1, as cited in the IDS).
Regarding claim 9, Perlstein et al teaches a method for treating a mammal identified as (a) having a CDG (see Abstract, which discloses increasing glycosylation and treating congenital disorders of glycosylation, such as CDG) and (b) having a biological sample containing an elevated level of one or more polyols, relative to the level of said one or more polyols in a biological sample from a control mammal not having said CDG (see [0082], which states that aldose reductase inhibitors (ARI) may reduce the flux of glucose through the polyol pathway, which can lead to inhibition of tissue accumulation of sorbitol and fructose and prevention of reduction of redox potentials. See also [0101]-[0102], which discloses an embodiment of methods for treating increasing glycosylation in a patient comprising administering a therapeutically effective amount of a compound, where increasing glycosylation provides increased levels of glycosylated glycoproteins, lysosomal enzymes, or serum proteins as compared to levels of glycoproteins, lysosomal enzymes, or serum proteins prior to administration), wherein said method comprises administering to said mammal a dose of an aldose reductase inhibitor (ARI) that is increased as compared to a dose of said ARI that would be administered to a mammal identified as having said CDG and as having a biological sample that does not contain an elevated level of said one or more polyols, relative to the level of said one or more polyols in said biological sample from said control mammal (see [0082], [0118], which states that aldose reductase inhibitors (ARI) may reduce the flux of glucose through the polyol pathway, which can lead to inhibition of tissue accumulation of sorbitol and fructose and prevention of reduction of redox potentials. The specific dose level of a compound of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. See also [0083], [0086] and [0091], which discloses embodiments of pharmaceutical compositions that comprise one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients, where the aldose reductase inhibitor (ARI) is Compound 1 or a pharmaceutically acceptable salt thereof in some embodiments. In other embodiments, such as using and treating with excipients, it may include polyols such as sorbitol and mannitol).
While Perlstein et al doesn’t explicitly teach that the method for treating a mammal identified as having CDG involves administering to said mammal a dose of an aldose reductase inhibitor (ARI) that is increased as compared to a dose of said ARI that would be administered to a mammal identified as having said CDG, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the different embodiments methods for treating increasing glycosylation (see [0101]-[0102]), pharmaceutical compositions used in increasing glycosylation, and excipients including polyols (see [0083], [0086] and [0091]) as taught by Perlstein et al. above, in order to achieve the expected result of having a biological sample containing an elevated level of one or more polyols, relative to the level of said one or more polyols in a biological sample from a control mammal not having said CDG and then treating the subject with an increased amount of ARI for the benefit of effectively treating the subject with CDG.
Regarding claim 10, Perlstein et al teaches wherein said mammal to which said increased dose of ARI is administered is a human (see [0065], [0118], the specific dose level of a compound of the present disclosure for any particular subject will depend upon a variety of factors. “Subject” or “patient” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject or patient is a human). Therefore, Perlstein et al teaches the exact limitations of claim 10.
Regarding claim 11, Perlstein et al teaches wherein said CDG is a Type II CDG (see [0107], the congenital disorder of glycosylation is a Type II disorder). Therefore, Perlstein et al teaches the exact limitations of claim 11.
Regarding claim 12, Perlstein et al teaches wherein said CDG is PMM2- CDG (see [0099], PMM2-CDG is the most common disorder of glycosylation with more than 800 patients reported worldwide). Therefore, Perlstein et al teaches the exact limitations of claim 12.
Regarding claim 15, Perlstein et al teaches wherein said biological sample is a urine sample or a blood sample (see [0067], exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva). Therefore, Perlstein et al teaches the exact limitations of claim 15.
Regarding claim 16, Perlstein et al teaches wherein said ARI comprises epafrestat, AT007, alrestatin, benurestat, epafrestat, fidarestat, imirestat, lidorestat, minalrestat, ponalrestat, ranirestat, risarestat, sorbinil, tolrestat, zenarestat, or zopolrestat (see [0082], Non-limiting examples of an aldose reductase inhibitor include but are not limited to alrestatin, epalrestat, fidarestat, imirestat, lidorestat, minalrestat, ponalrestat, ranirestat, salfredin Bn, sorbinil, tolrestat, zenarestat, and zopolrestat). Therefore, Perlstein et al teaches the exact limitations of claim 16.
Regarding claim 18, Perlstein et al teaches wherein said increased dose is from about 0.5 mg/kg/day to about 5 mg/kg/day (see [0118], [0122], dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). The method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week). Therefore, Perlstein et al teaches the exact limitations of claim 18.
Regarding claim 19, Perlstein et al teaches wherein said increased dose is at least about 50% greater than a dose of the ARI previously administered to said mammal (see [0122], the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week). Therefore, Perlstein et al teaches the exact limitations of claim 19.
Claims 13, 17, 20-24 and 26-30 are rejected under 35 U.S.C. 103 as being unpatentable over Perlstein et al as applied to claim 9 and claim 20 above, and further in view of Williams et al (“Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: update of 34 patients”, as cited in the IDS).
Regarding claim 13, Perlstein et al teaches aldose reductase inhibitors that may reduce the flux of glucose through the polyol pathway, which can lead to inhibition of tissue accumulation of sorbitol and fructose and prevention of reduction of redox potentials (see Perlstein et al, [0082]).
Perlstein et al fails to teach wherein said one or more polyols comprise one or more of mannitol, sorbitol, maltitol, xylitol, and erythritol.
However, in the analogous art of the overview of transaldolase deficiency and evaluation of the endocrine function, Williams et al teaches determining transaldose deficiency in patients, using polyol analysis performed in urine, plasma, and cerebral spinal fluid. Abnormal polyols and/or seven carbon sugars were detected in urine: increased excretion of eythritol, arabitol, ribitol, sedohepitiol, perseitol, sedoheptulose, mannoheptulose, and sedoheptulose-7P (see Williams et al, Laboratory Diagnosis). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the polyol pathway of Perlstein et al to include the detected polyols (as taught by Williams et al), for the benefit of determining whether CDG patients can be further diagnosed for transaldose deficency to adjust patient treatment plan accordingly (see Williams et al, Diagnosis).
Regarding claim 17, Perlstein et at teaches biological fluid samples, including blood, cerebrospinal fluid, urine, and saliva, where it can be examined for compounds, which can further be characterized to examine the safety or tolerance dosage in humans or non-human dosages (see Perlstein et al, [0067]).
Perlstein et al fails to teach wherein the elevated level of said one or more polyols is increased by at least 10% as compared to the level of said one or more polyols in the biological sample from said control mammal.
However, Williams et al teaches plasma investigations that were performed on 11 patients, and showed mild elevations of erythritol, arabitol, and ribitol. In one patient, polyols in cerebro-spinal fluid were measured and showed a mild elevation of ribitol (19μmol/l; reference values <6) (See Williams et al, Biochemical Analysis). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the examination of biological fluids of Perlstein et al to incorporate the investigations of abnormal polyols levels (as taught by Williams et al), for the benefit of determining whether CDG patients can be further diagnosed for transaldose deficency to adjust patient treatment plan accordingly (see Williams et al, Diagnosis).
Regarding claim 20, Perlstein et al teaches a method of increasing glycosylation and treating congenital disorders of glycosylation (see Perlstein et al, Abstract), using aldose reductase inhibitors, which may reduce the flux of glucose through the polyol pathway, which can lead to inhibition of tissue accumulation of sorbitol and fructose and prevention of reduction of redox potentials (see Perlstein et al, [0082]). The specific dose level of ARI for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy (see Perlstein et al, [0118]).
Perlstein fails to explicitly to teach measuring a level of one or more polyols in a biological sample from said mammal, and determining that a measured level of at least one of said one or more polyols is elevated relative to a level of the one or more polyols in a biological sample from a control mammal that does not have said CDG.
However, Williams et al teaches measuring sugars and polyols in urine and/or plasma by gas chromatography (see Williams et al, Biochemical Studies). The polyol analysis found that all transaldose deficiency patients had abnormal polyols and/or seven-carbon sugars that were detected in their urine: increased excretion of eythritol, arabitol, ribitol, sedohepitiol, perseitol, sedoheptulose, mannoheptulose, and sedoheptulose-7P (see Williams et al, Biochemical Analysis). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of Perlstein et al to incorporate the polyol analysis (as taught by Williams et al), for the benefit of determining whether CDG patients can be further diagnosed for transaldose deficency to adjust patient treatment plan accordingly (see Williams et al, Diagnosis).
Regarding claim 21, the combination of Perlstein et al and Williams et al teaches wherein said mammal to which said increased dose of ARI is administered is a human (see [0065], [0118], the specific dose level of a compound of the present disclosure for any particular subject will depend upon a variety of factors. “Subject” or “patient” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject or patient is a human). Therefore, Perlstein et al teaches the exact limitations of claim 21.
Regarding claim 22, the combination of Perlstein et al and Williams et al teaches wherein said CDG is a Type II CDG (see [0107], the congenital disorder of glycosylation is a Type II disorder). Therefore, Perlstein et al teaches the exact limitations of claim 22.
Regarding claim 23, the combination of Perlstein et al and Williams et al teaches wherein said CDG is PMM2- CDG (see [0099], PMM2-CDG is the most common disorder of glycosylation with more than 800 patients reported worldwide). Therefore, Perlstein et al teaches the exact limitations of claim 23.
Regarding claim 24, Perlstein et al teaches aldose reductase inhibitors that may reduce the flux of glucose through the polyol pathway, which can lead to inhibition of tissue accumulation of sorbitol and fructose and prevention of reduction of redox potentials (see Perlstein et al, [0082]).
Perlstein et al fails to teach wherein said one or more polyols comprise one or more of mannitol, sorbitol, maltitol, xylitol, and erythritol.
However, Williams et al teaches determining transaldose deficiency in patients, using polyol analysis performed in urine, plasma, and cerebral spinal fluid. Abnormal polyols and/or seven carbon sugars were detected in urine: increased excretion of eythritol, arabitol, ribitol, sedohepitiol, perseitol, sedoheptulose, mannoheptulose, and sedoheptulose-7P (see Williams et al, Laboratory Diagnosis). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the polyol pathway of Perlstein et al to include the detected polyols (as taught by Williams et al), for the benefit of determining whether CDG patients can be further diagnosed for transaldose deficency to adjust patient treatment plan accordingly (see Williams et al, Diagnosis).
Regarding claim 26, the combination of Perlstein et al and Williams et al teaches wherein said biological sample is a urine sample or a blood sample (see [0067], exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva). Therefore, Perlstein et al teaches the exact limitations of claim 26.
Regarding claim 27, the combination of Perlstein et al and Williams et al teaches wherein said ARI comprises epafrestat, AT007, alrestatin, benurestat, epafrestat, fidarestat, imirestat, lidorestat, minalrestat, ponalrestat, ranirestat, risarestat, sorbinil, tolrestat, zenarestat, or zopolrestat (see [0082], Non-limiting examples of an aldose reductase inhibitor include but are not limited to alrestatin, epalrestat, fidarestat, imirestat, lidorestat, minalrestat, ponalrestat, ranirestat, salfredin Bn, sorbinil, tolrestat, zenarestat, and zopolrestat). Therefore, Perlstein et al teaches the exact limitations of claim 27.
Regarding claim 28, Perlstein et at teaches biological fluid samples, including blood, cerebrospinal fluid, urine, and saliva, where it can be examined for compounds, which can further be characterized to examine the safety or tolerance dosage in humans or non-human dosages (see Perlstein et al, [0067]).
Perlstein et al fails to teach wherein the elevated level of said one or more polyols is increased by at least 10% as compared to the level of said one or more polyols in the biological sample from said control mammal.
However, Williams et al teaches plasma investigations that were performed on 11 patients, and showed mild elevations of erythritol, arabitol, and ribitol. In one patient, polyols in cerebro-spinal fluid were measured and showed a mild elevation of ribitol (19μmol/l; reference values <6) (See Williams et al, Biochemical Analysis). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the examination of biological fluids of Perlstein et al to incorporate the investigations of abnormal polyols levels (as taught by Williams et al), for the benefit of determining whether CDG patients can be further diagnosed for transaldose deficency to adjust patient treatment plan accordingly (see Williams et al, Diagnosis).
Regarding claim 29, the combination of Perlstein et al and Williams et al teaches wherein said increased dose is from about 0.5 mg/kg/day to about 5 mg/kg/day (see [0118], [0122], dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). The method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week). Therefore, Perlstein et al teaches the exact limitations of claim 29.
Regarding claim 30, the combination of Perlstein et al and Williams et al teaches wherein said increased dose is at least about 50% greater than a dose of the ARI previously administered to said mammal (see [0122], the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week). Therefore, Perlstein et al teaches the exact limitations of claim 30.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tracy C Colena whose telephone number is (571)272-1625. The examiner can normally be reached Mon-Thus 8:00am-5:00pm.
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/TRACY CHING-TIAN COLENA/Examiner, Art Unit 1797
/JENNIFER WECKER/Primary Examiner, Art Unit 1797