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 .
DETAILED ACTION
Claims 1-2, 4-5, 7, 9, 14, 17, 19-20, 22, 24, 29, 31-34, 39, 43, and 48 are currently pending and are examined on the merits herein.
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. Thus, the priority date of the instant invention is November 09th, 2020.
IDS
The information disclosure statements (IDS) submitted on 04/26/23, 01/31/24, and 11/21/2024 are acknowledged and have been entered. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Objections
Claims 2, 29, and 48 are objected to as claim 2 recites the term “or in an improvement…” on line 4, the recitation of “in” is redundant as the claims recite a list of improvement to be measured by various scales. Such word should be deleted from the claim.
Additionally, claim 29, recite the terms “where in” as two separate terms and should be combined.
Claim 48 is dependent on a cancelled claim 45. The dependency should change to claim 1.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 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 2, 24, and 43 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 2 recites the limitation "the Dermatology Life Quality Index..” in claim 2, line 4; in claim 2 lacks antecedent basis; the recitation of “the improvement to moderate…” in claim 43, line 2; the recitation of “at least one interruption period..” in claim 9 which now broadens the claim; and the recitation of “at least one of the interruption…” in claim 24, line 2 now broadens claim 24. Specifically, the claims contains no earlier recitation or limitation of said terms and thus are unclear as to what element the limitations were making reference to. As a result, there is insufficient antecedent basis for these limitations in the claims.
Additionally, claims 9 and 24 broadens the scope of a previously narrowed recitation thereby creating an indefiniteness in the claims. As a result of the above inconsistencies, the aforementioned claims are unable to be examined as disclosed given that the scope of the claimed subject matter would not be able to be determined by one of ordinary skill in the art.
Non-Statutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 5, 9, 19, 22, 24, 32-33, and 39 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 3-5, 7, and 16-17 of U.S. Patent No. 12,156,866 (hereinafter Christopher US Patent No. ‘866). Although the conflicting claims are not completely identical, they are not patentably distinct from each other because both applications are directed to a method of treating a disease or a condition related to S1P1 receptors, the method comprising administering Compound 1 or etrasimod to a subject in need thereof in similar dosage amounts. The claimed invention is directed to a subgenus of a method of treating moderate to severe Atopic Dermatitis (AD) comprising administering etrasimod by identifying a threshold ALC, ceasing administration in case of an infection and then continuing after an interruption period of time.
Christopher ‘866 recites a broad genus of a method of treating a disease or a condition mediated by S1P1 receptors comprising administering the same compound 1.
While the instant invention is silent on the fed/fasted ratio and the Cmax, the examiner contends that the term “comprising: does not exclude additional step such as determining fed/fast ratio and Cmax concentration.
Moreover, discontinuation of the treatment is obvious as AD and treatment with Compound 1 are associated with potential lymphopenia and thus obvious to discontinue treatment if the adverse events are encountered.
Thus, the aforementioned claims of the instant application are rendered obvious as discussed hereinabove and are prima facie obvious over the cited claims of corresponding U.S. Patent No. 12,156,866.
Claim Rejections - 35 USC § 112
Notice of AIA Status
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.
Claims 1-2, 4-5, 7, 9, 14, 17, 19-20, 22, 24, 29, 31-34, 39, 43, and 48 are 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 ameliorating moderate to severe atopic dermatitis comprising administering etrasimod, does not reasonably provide enablement for inhibiting or arresting the development of atopic dermatitis. 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..
The instant claims are drawn to a method of treating moderate to severe atopic dermatitis comprising administering etrasimod, or a pharmaceutically acceptable salt thereof, to a patient in need thereof; identifying a threshold absolute lymphocyte to count (ALC) in the patient; ceasing administration of the etrasimod, or a pharmaceutically acceptable salt thereof, for an interruption period of time; and after ceasing administration for the interruption period of time, continuing to administer the etrasimod, or a pharmaceutically acceptable salt thereof, for a continuation period of time; wherein the patient in need thereof experiences an improvement in moderate to severe atopic dermatitis. The instant specification fails to provide information that would allow the skilled artisan to practice the inhibition of the development of atopic dermatitis.
[In re Sichert, 196 USPQ 209 (CCPA 1977)]
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).1
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative
skill level
The invention relates to a method of treating moderate to severe atopic dermatitis comprising administering etrasimod, or a pharmaceutically acceptable salt thereof, to a patient in need thereof; identifying a threshold absolute lymphocyte to count (ALC) in the patient; ceasing administration of the etrasimod, or a pharmaceutically acceptable salt thereof, for an interruption period of time; and after ceasing administration for the interruption period of time, continuing to administer the etrasimod, or a pharmaceutically acceptable salt thereof, for a continuation period of time; wherein the patient in need thereof experiences an improvement in moderate to severe atopic dermatitis. The relative skill of those in the art is high, that of an MD or PHD. That factor is outweighed, however, by the unpredictable nature of the art. The specification specifically teaches that the term treating include inhibiting the disease or condition or arresting (i.e. stopping) the development of the disease or condition (see spec. pg. 8, last paragraph). However, attention is directed to Bin et al. who teaches about the genetic and epigenetic factors involved in atopic dermatitis (i.e. eczema). As illustrative of the state of the art, the examiner cites Bin et al. (Allergy Asthma Clin. Immunol., 2016, Vol. 12, No. 52, pgs. 1-14) who teaches that atopic dermatitis is a chronic inflammatory disease caused by a complex interaction of genetic, immune and environmental factors (see abstract). Importantly, Bin et al. teach that FLG mutation is the most replicated atopic dermatitis (AD) gene association followed by genes in the Th2 signaling pathway and interleukin genes and that vitamin D signaling pathway and polymorphisms in the vitamin D receptor were found to be associated with AD severity (see results section). Consequently, Bin et al. suggest epigenetic studies indicate that the modifications of genes play a role in the pathogenesis of AD. Since both genetic and epigenetic factors are at play as stipulated by Bin et al., the examiner maintains that arresting the development of the disease or condition is highly unlikely.
2. The breadth of the claims
The claims are thus very broad insofar as they recite that the “treatment” encompasses arresting or inhibiting AD from developing irrespective of the etiology of the disease or condition. While “alleviation or amelioration of AD” might theoretically be possible by administering etrasimod as delineated in claim 1, as a practical matter it is nearly impossible to achieve inhibition of such disease and/or condition with said compound. Moreover, nowhere in the specification did Applicant demonstrate inhibiting the condition or disease from occurring.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides no direction or guidance for the use of etrasimod inhibiting the development of AD. While specific guidance is provided concerning treatment with etrasimod resulting in improvement of patient’s condition and in reduction of vIGA score (i.e. determining scale to test severity of AD).
4. The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence demonstrating amelioration of AD, no one skilled in the art would accept the assertion that the instantly claimed compound, etrasimod, could be predictably used for inhibiting or arresting the disease as inferred by the claims and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 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(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1-2, 4-5, 7, 9, 14, 19-20, 22, 24, 29, 32-33, 39, 43, and 48 are rejected under 35 U.S.C. 103(a) as being obvious over Glicklich et al. (U.S. 2018/0263958 A1, cited on an IDS 1449) in view of Bakker et al. (J. of Dermatological Treatment, 2018, Vol. 29, Iss. 7, pgs. 682-687) and Worm et al. (JAMA Dermatology, Dec. 2019, Vol. 156, Iss. 2, pgs. 131-141).
Glicklich et al. teach methods of treatment of a sphingosine 1-phospate subtype 1 (S1P1) receptor-associated disorder comprising prescribing and/or administering to an individual in need thereof a standard dose of Compound 1 or etrasimod or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in an amount equivalent to about 1.5 to about 2.5 mg or 0.5 to about 2.5 mg of etrasimod in diseases mediated by lymphocytes including autoimmune and/or inflammatory disorder (instant claims 5, 22, and 39; see abstract and paragraphs 0006-0008 and 0023). Additionally, Glicklich et al. teach that the dose administered achieves a target reduction in peripheral blood lymphocyte counts wherein such reduction can be less than 1000 lymphocytes per microliter (i.e. inclusive of ALC less than 500/mm3; instant claim 7) and the target dose may vary depending on the nature or severity of the disease and can be administered once daily to the individual (see paragraphs 0063 and 00153). Importantly, Glicklich et al. teach that the compounds of the invention are S1P1 receptor agonists that are useful in treating various S1P1 receptor mediated diseases or disorders including atopic dermatitis (see paragraph 0265). Glicklich et al. further teach that an individual can be administered one or more doses each of which is less than the standard dose for a first period of time prior to prescribing or administering to the individual Compound 1 or etrasimod at the standard dose (i.e. inclusive of administration before interruption and continuation time period; see paragraph 0133). The treatment also encompasses reduction of lymphocyte count and further comprises monitoring for adverse effects and optionally interrupting or terminating the administration of compound 1 (i.e. cessation of treatment and then continuing administering Compound 1; instant claim 1; paragraphs 0134-0135). Of interest, Glicklich et al. teach that the treatment results in maintaining clinical remission of said disease (see paragraph 0140). Various dosage amounts are envisioned including equivalent amounts of about 2mg to about 2.5 mg (see paragraphs 0177 and 0298).
Glicklich et al. do not teach identifying a threshold absolute lymphocyte count. Additionally, Glicklich et al. do not teach measuring scale utilized for improvement in atopic dermatitis. Glicklich et al.do not teach that the interruption period of time is at least one week.
Bakker et al. teach that atopic dermatitis (AD) is associated with low lymphocyte counts (i.e. below 0.8x109/L; see pg. 683, right col. and pg. 686). In fact, patient 11 (see fig 1K) was found to have lymphopenia (i.e. low lymphocyte count) before treatment and persisted even with treatment (see pg. 683). Additionally, Bakker et al. found that all total white blood cell counts remain within normal range at the time of decreased lymphocyte count wherein lymphocytes counts were all lower limit than normal (see fig. 2). This suggests that determining the absolute lymphocyte count would be obvious to perform as such levels may indicate severity of disease and/or potential toxicity or patient’s response to therapy despite the presence of lymphopenia.
Worm et al., on the other hand, was provided to demonstrate the various disease severity scale and dosage regimen utilized when treating AD. Specifically, Worm et al. teach that a study was conducted wherein dupilumab was administered in moderate to severe AD patients wherein improvement was recorded as achieving an Investigator’s Global Assessment Score (IGA) of 0 or 1 (i.e. increase in severity would therefore be higher 2 or more) or wherein improvement in Eczema Area and Severity Index (EASI-75) is 75% (instant claims 2, 14, 29, and 48; see pg. 132, right col.). Other outcomes measures were also used to measure improvement of disease after treatment including pruritus (instant claim 43), Patient-Oriented Eczema Measure (POEM) of 0.3 vs. -7.0 for placebo, Dermatology Life Quality Index (DLQI) of. 0.2 vs. -3.1 for placebo (see pg. 134 and pg. 137, table 2). Worm also teaches that patients sometimes discontinue treatment due to presence of adverse effects such as herpes simplex virus, skin infections, or respiratory infection (instant claims 32-33; see pg. 139, right col. and pg. 140, table 3). Overall, Worm et al. demonstrated that patients receiving short term regimen had nominally significantly greater improvements vs. placebo (see pg. 139, left col. last paragraph).
Consequently, it would have been obvious to one of ordinary skill in the art at the time the invention was made to identify an ALC threshold as a low count can lead to lymphopenia and thus subject the individual to infections as discussed in Bakker. One of ordinary skill in the art would have found it obvious to monitor for infections such as skin infections or herpes simplex virus since Worm et al. teach that such infections can arise due to treatment. Additionally, one of ordinary skill in the art would have found it obvious to interrupt treatment for a determined period of time including at least one week as taught by Glicklich et al. since treatment interruption may be warranted for some patients whose ALC is extremely reduced thereby allowing time to recover and then continue for a period of time with etrasimod for treatment of AD. Moreover, one skilled in the art would have looked to various measuring scales including EASI score and vIGA score since Worm et al. teach that such scales are a measurement of the efficacy of the treatment and reduction of the skin lesions associated with the disease. A reasonable expectation of success would have ensued since Glicklich et al. teach that Compound 1 or etrasimod of the invention can lead to treatment of various S1P associated lymphocyte disorders including atopic dermatitis (AD).
Claims 17, 31, and 34 are rejected under 35 U.S.C. 103(a) as being obvious over Glicklich et al. (U.S. 2018/0263958 A1, cited on an IDS 1449) in view of Bakker et al. (J. of Dermatological Treatment, 2018, Vol. 29, Iss. 7, pgs. 682-687) and Worm et al. (JAMA Dermatology, Dec. 2019, Vol. 156, Iss. 2, pgs. 131-141) as applied to claims1-2, 4-5, 7, 9, 14, 19-20, 22, 24, 29, 32-33, 39, 43, and 48 in view of Czarnowicki et al. (Allergy, European Journal and Clinical of Allergy and Clinical Immunology, 2017, Vol. 72, Iss. 3, pgs. 325-510) and Washington State Health Care Authority (Atopic Dermatitis Agents, May 1, 2020, pgs. 1-8).
The Glicklich, Bakker, and Worm references are as discussed above and incorporated by reference herein. However, Glicklich, Bakker, and Worm do not teach testing circulating blood level of lymphocytes or the body surface area of atopic dermatitis greater than 10%.
Czarnowicki et al. teach that cutaneous lymphocyte-associated antigen (CLA+) T cells are specialized for skin homing and are the main types of T-cell population in atopic dermatitis (AD; see abstract). Importantly, the study teaches that circulating CLA+ T cells may be a reliable surrogate marker of the inflammatory events occurring in the skin and thus, the evaluation of CLA+ T cells in the blood may eliminate the need for skin biopsies (see abstract). Importantly, Czarnowicki et al. also teach that circulating CLA + T cells are functionally related to AD and shows phenotypic changes during clinical AD manifestation (see pg. 367).
Washington Health Care Authority is provided to demonstrate that moderate to severe chronic atopic dermatitis (AD) is characterized by body surface areas involvement of at least 10% (see pg. 1).
Consequently, it would have been obvious to one of ordinary skill in the art at the time the invention was made to determine the BSA level of a patient in order to determine the severity of AD and the proper dosage regimen including interruption time period if such patient develops an adverse effect. Additionally, one of ordinary skill in the art would have found it obvious to monitor the level of circulating blood level of lymphocytes as they are biomarkers reflecting relevant phenotypic changes that are occurring and identifying the level of inflammation that is present in the disease. One skilled in the art who follows the teaching would have had a reasonable expectation of success as such markers would have informed the practitioner the type of treatment needed and the regimen needed depending on the severity of the disease.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Director Patricia Mallari whose telephone number is 571-272-4729. The Supervisory Primary Examiner can normally be reached on 12:00-8:00 PM EST M-F at 571-270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
1 As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is “undue”, not “experimentation”.