NON-FINAL REJECTION
This application, filed Jan. 23, 2024, is a continuation of 14/449,513, filed Aug. 1, 2014, and claims benefit of priority to Provisional Application 61/861,256, filed Aug. 1, 2013.
Claims 49-68, as amended, are pending.
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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on Apr. 30, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 U.S.C. § 112(d) – Improper Dependency
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 54-55 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.
Specifically, claims 54 and 55 recite the method of claim 49, wherein the predetermined time interval length is decreased based on the patient genotype tested in (a); or the predetermined time interval length is increased based on the patient genotype tested in (a), respectively.
However, claim 49 part (c) already recites these limitations:
(c) periodically testing the patient for a blood lymphocyte concentration over a predetermined time interval length, wherein the predetermined time interval length is increased or decreased based on the patient genotype tested in (a).
Thus, claims 54-55 fail to further limit claim 49.
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.
Claim Rejections - 35 USC § 103
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.
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.
Claims 49-68 are rejected under 35 U.S.C. 103 as being unpatentable over Gangakhedkar et al. (US Pub. 2010/0048651), in view of Gambichler et al. (JEADV 28(5):574-580 (2014)) and Roll et al. (Indian J Dermatol Venereol Leprol 73:133-7 (2007)) (all cited on the IDS dated 4/30/2024), as evidenced by Cleveland Clinic (Lymphopenia (2023), cited on PTO-892).
Gangakhedkar et al. disclose and claim methods of treating a disease in a patient, including multiple sclerosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of a composition comprising a prodrug of hydrogen methyl fumarate (abstract; Description 2; Example 54; paras. [0344]-[0346]; claims 20-25).
The prodrug includes the claimed compound, (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (para. [0105]; Example 1; claim 9), a.k.a. tepilamide fumarate, having the structural formula,
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.
The compounds of Gangakhedkar et al. are disclosed to be administered at a dose from about 10 mg to about 4 g per day (para. [0335]); and can be administered in a unit dosage form as a single daily dose, or twice per day (para. [0326]).
Thus, Gangakhedkar et al. disclose methods for treating multiple sclerosis in a patient in need thereof, comprising administering (N,N-diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (tepilamide fumarate) to the patient, in a once or twice daily dose ranging from about 10 mg to about 4 g, as recited by claim 49 (part (b)) and claims 50-52.
The compounds of Gangakhedkar et al. are disclosed in oral dosage forms, including sustained release oral dosage forms (para. [0329]-[0330]), as recited by claims 63-65.
Gangakhedkar et al. teach that sustained release oral dosage forms may be used to release
drugs over a prolonged time period and are useful when it is desired that a drug or drug form be delivered to the lower gastrointestinal tract. Sustained release oral dosage forms and methods of preparing them are well known in the art, and include diffusion-controlled systems such as reservoir devices and matrix devices, dissolution-controlled systems, osmotic systems, and erosion-controlled systems, implicitly disclosing sustained release oral dosage forms which comprise an enteric coating, as well as those which do not, as recited by claims 66-67.
The compounds of Gangakhedkar et al. may be administered to a patient together
with another compound for treating, e.g., multiple sclerosis, which may be included in the same dosage form or provided in a separate dosage form (para. [0372]-[0374]), as recited by claim 68.
Gangakhedkar et al. differs from the instant claims in that Gangakhedkar et al. do not disclose steps (a), (c), (d), or (e), as recited by claim 49; or the testing details recited by claims 53-62.
The instant specification discloses that enzyme level propensity testing, as recited in step (a) of claim 49, can be either genotype or phenotype testing. For genotype testing, the testing comprises determining whether the patient exhibits a GSTT1*0/0 genotype, a GSTT1*A/A genotype or a GSTT1*A/0 genotype. Phenotype testing comprises measuring the amount of S-methyl glutathione formed upon exposure of patient hemoglobin or lymphocytes to methyl chloride (para. [0011]). Both of these are disclosed by Gambichler et al.
Gambichler et al. treated 106 psoriasis patients with a fumaric acid ester (FAE), then performed glutathione S-transferase theta 1 enzyme (GSTT1) genotyping and phenotyping.
Following PCR genotype testing, the distribution of GSTT1 genotypes was *A/*A (31%), *A/*0 (49%), and *0/*0 (20%) (abstract), as recited by claim 56. This genetic polymorphism was not found to influence response to treatment with FAE.
For the phenotype testing, Gambichler et al. used an HPLC assay to analyze erythrocyte lysate samples for 5-methylglutathione (MeSG) formation rates following exposure to 10,000 ppm methyl chloride (MeCl) (p. 3, left col.), as recited by claim 53.
Gambichler et al. report an association between the frequent occurrence of lymphocyte reduction (>50%) in patients with *0/*0 GSTT1 genotype, which is a predictor of marked reduction of lymphocyte counts under FAE therapy (abstract). A marked decline of circulating lymphocytes can be predicted by the presence of *0/*0 GSTTI status; i.e., the likelihood of substantial decrease in lymphocyte counts under FAE treatment is increased sixfold in patients with *0/*0 GSTTl status (p. 6, left col.).
Thus, significant lymphocyte reduction was a known side effect of treatment with fumaric acid esters, which was known to depend on a patient's GSTT1 genotype.
Therefore, before administering a fumaric acid ester to a patient, it would have been predictable to an ordinarily skilled clinician to test the patient for a propensity for a deficiency in tissue GSTT1 levels to determine the patient genotype, as recited in part (a) of claim 49.
In addition, Roll et al. disclose that leukopenia (particularly lymphopenia, a.k.a. lymphocytopenia) is a concern during long-term FAE treatment (p. 134, left col.), as it is a frequent side effect of treatment with fumaric acid esters (Table 3, shown below):
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A decrease of lymphocytes below 500/mm3 (500 μl) should lead to dosage reduction or withdrawal of treatment (p. 135, right col.; p. 136, left col.), such that monitoring of full blood cell count during treatment is necessary (p. 136, right col.).
Therefore, it would have been predictable to an ordinarily skilled clinician to periodically test the patient for a blood lymphocyte concentration over a predetermined time interval based on the patient's GSTT1 genotype, as recited in part (c) of claim 49, and claims 54-55.
The cited references do not specify that administration should be suspended if the patient's blood lymphocyte concentration is below 1500 cells/μl for an adult, or below 3000 cells/μl for a child; or to continue or resume administration when the patient's blood lymphocyte concentration is above these levels, as recited in parts (d) and (e) of claim 49.
However, it would have been predictable to an ordinarily skilled clinician to arrive at these cutoffs by routine experimentation, because they fall near the low end of the normal range of blood lymphocyte levels, which was known in the art.
For example, as evidenced by Cleveland Clinic (p. 1), normal lymphocyte levels differ for adults and children. In adults, the normal range is between 1,000 and 4,800 lymphocytes per microliter of blood; less than 1,000 lymphocytes per microliter of blood indicates lymphopenia.
In children, the normal range is between 3,000 and 9,500 lymphocytes per microliter of blood. Low levels (or lymphopenia) depend on the child’s age: children under 2 years old have lymphopenia if they have less than 3,000 lymphocytes per microliter of blood.
Thus, suspending FAE administration when an adult patient's blood lymphocyte concentration falls below 1500 cells/μl, or when a pediatric patient's blood lymphocyte concentration falls below 3000 cells/μl, follows the teachings of Roll et al. to monitor lymphocyte counts and to withdraw treatment before lymphopenia fully develops.
Roll et al. do not specify the duration of the time intervals between each test of the patient's blood lymphocyte concentration, as recited by claims 57-62.
However, it would have been predictable to an ordinarily skilled clinician as of the filing date to adjust the testing frequency based on the patient's genotype with a reasonable expectation of success, because fumaric acid esters were known to cause decreases in blood lymphocyte concentration; variations would be expected from patient to patient; a decrease would be expected in patients with the GSTT1 *0/*0 genotype; and optimizing testing intervals based on patient-specific variables is a routine aspect of therapeutic drug monitoring.
As recognized by MPEP §2143, combining prior art elements according to known methods to yield predictable results would motivate the skilled artisan to modify the references with a reasonable expectation of success. The rationale to support a conclusion of prima facie obviousness is that all the claimed elements were known in the prior art, and a skilled artisan could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. See KSR Int'l Co. v. Teleflex Inc. (550 U.S. 398, 409).
Citation of Additional Prior Art
Additional references made of record are considered pertinent to applicant's disclosure:
US Pub. 2014/0275048 and US Pub. 2014/0275205 (cited on PTO-892).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 10:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA E. TOWNSLEY/Examiner, Art Unit 1629
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