DETAILED ACTION
Notice of Pre-AIA or AIA Status
The inventor or joint inventor should note that the instant invention, 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 1, 5-12, 27, 28 and 31-35 are pending in the instant invention. According to the Amendments to the Claims, filed March 14, 2024, claims 1, 5-12, 27, 28, 31, 32, 34 and 35 were amended and claims 2-4, 13-26, 29 and 30 were cancelled.
Status of Priority
This invention is a Divisional (DIV) of US Application No. 17/545,494, filed December 8, 2021 and now US 11,952,346, which claims priority under 35 U.S.C. § 119(e) to US Provisional Application No. 63/123,411, filed December 9, 2020.
Restrictions / Election of Species
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The forthcoming first Office action and prosecution on the meris includes (1) claims 1, 5-12, 27, 28 and 31-35, drawn to a method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), shown to the right.
Thus, a first Office action and prosecution on the merits of claims 1, 5-12, 27, 28 and 31-35 is contained within.
Specification Objection - Disclosure
The following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the inventor’s or joint inventor’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility invention should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase Not Applicable should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR
DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A
COMPACT DISC.
(f) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art (including information disclosed under 37 CFR 1.97
and 1.98).
(g) BRIEF SUMMARY OF THE INVENTION.
(h) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(i) DETAILED DESCRIPTION OF THE INVENTION.
(j) CLAIM OR CLAIMS (commencing on a separate sheet).
(k) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(l) SEQUENCE LISTING (See MPEP § 2424 and 37 CFR 1.821-1.825).
The inventor or joint inventor is advised to format the specification according to 37 CFR 1.77(b) above and 37 CFR 1.77(c). Revisions should particularly include and/or address: a) section headings (b-i), where applicable; and b) bold-type, underline, and/or upper case formatting. Appropriate correction may be required.
Specification Objection - Title
The inventor or joint inventor is reminded of the proper content of the title of the invention.
The title of the invention should be brief, but technically accurate and descriptive and should contain fewer than 500 characters. See 37 CFR 1.72(a) and MPEP § 606.
The title of the invention is not technically accurate and descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. In the revised title, the examiner suggests additionally identifying the substituted cyclohexanes having the structure (Ib).
The following title is suggested: SUBSTITUTED CYCLOHEXANES AS MODULATORS OF MAS-RELATED G-PROTEIN RECEPTOR X2.
Appropriate correction is required.
Specification Objection - Abstract
The inventor or joint inventor is reminded of the proper content of an abstract of the disclosure.
With regard particularly to chemical patents, for compounds or compositions, the general nature of the compound or composition should be given as well as the use thereof, e.g., The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics. Exemplification of a species could be illustrative of members of the class. For processes, the reactions, reagents and process conditions should be stated, generally illustrated by a single example, unless variations are necessary. See MPEP § 608.01(b), Section B.
The abstract of the disclosure is objected to because it fails to exemplify any members or formulae illustrative of its class. Correction is required. See MPEP § 608.01(b).
The examiner suggests incorporating structure (Ib) into the abstract, to overcome this objection.
Claim Objections
Claim 1 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a) and/or 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation:
A method for modulating the activity of mas-related G-protein receptor X2 (MRGPRX2) or the activity of a mas-related G-protein receptor X2 (MRGPRX2) ortholog in a subject, wherein the method comprises administering to the subject in need thereof an effective amount of a compound having structure (Ib):
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(Ib)
or a pharmaceutically acceptable salt, isotope, hydrate, solvate, or stereoisomer thereof,
wherein:
Rw is H;
R2 is H;
Rd is CN;
Rz is H;
each R3 is independently H;
R1 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more independently selected Rq1 substituents;
each Rq1 is independently halo, CN, (CH2)nQ’, CHQ’R, C1-6 alkyl, haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)R, C(O)OR, NRR, NRC(NH)NRR, NRC(O)R, NRS(O)2R, OR, O(CH2)nR, O(haloalkyl), OC(O)R, S(O)2R, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each Q’ is independently CN, C1-6 alkyl, haloalkyl, C(O)OR’, NR’R’, NR’C(O)R’, NR’S(O)2R’, OR’, OC(O)R’, cycloalkyl, heterocyclyl, or aryl;
each R is independently H, halo, (CH2)nR’, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)NHR’, NH2, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
any two R groups, taken together with the nitrogen atom to which they are attached, independently form a heterocyclyl; and
each R’ is independently H, C1-6 alkyl, haloalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 5 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 1, wherein R1 is phenyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 6 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 5, wherein the phenyl is unsubstituted.
Appropriate correction is required. See MPEP § 2173.02.
Claim 7 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 5, wherein the phenyl is substituted with one or more independently selected Rq1 substituents.
Appropriate correction is required. See MPEP § 2173.02.
Claim 8 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method of claim 7, wherein each Rq1 is independently halo, CN, CHQ’R, NRR, NRC(O)R, NRS(O)2R, OR, or heterocyclyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 9 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 1, wherein R1 is heteroaryl, wherein the heteroaryl is optionally substituted with one or more independently selected Rq1 substituents.
Appropriate correction is required. See MPEP § 2173.02.
Claim 10 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 9, wherein the heteroaryl is unsubstituted.
Appropriate correction is required. See MPEP § 2173.02.
Claim 11 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation:
The method of claim 10, wherein the heteroaryl is substituted with one or more independently selected Rq1 substituents.
Appropriate correction is required. See MPEP § 2173.02.
Claim 12 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method of claim 11, wherein each Rq1 is independently C1-6 alkyl, NRR, or cycloalkyl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 27 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method of claim 1, wherein the compound is selected from the group consisting of:
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I-12,
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I-13,
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I-14,
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I-15,
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I-16,
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I-17,
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I-18,
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I-19,
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I-20,
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I-21,
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I-22,
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I-23,
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I-24, and
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I-25,
or a pharmaceutically acceptable salt, isotope, hydrate, or solvate thereof.
Appropriate correction is required. See MPEP § 2173.02.
Claim 28 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
A method for modulating the activity of mas-related G-protein receptor X2 (MRGPRX2) or the activity of a mas-related G-protein receptor X2 (MRGPRX2) ortholog in a subject, wherein the method comprises administering to the subject in need thereof an effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound having structure (Ib):
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(Ib)
or a pharmaceutically acceptable salt, isotope, hydrate, solvate, or stereoisomer thereof,
wherein:
Rw is H;
R2 is H;
Rd is CN;
Rz is H;
each R3 is independently H;
R1 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more independently selected Rq1 substituents;
each Rq1 is independently halo, CN, (CH2)nQ’, CHQ’R, C1-6 alkyl, haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)R, C(O)OR, NRR, NRC(NH)NRR, NRC(O)R, NRS(O)2R, OR, O(CH2)nR, O(haloalkyl), OC(O)R, S(O)2R, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each Q’ is independently CN, C1-6 alkyl, haloalkyl, C(O)OR’, NR’R’, NR’C(O)R’, NR’S(O)2R’, OR’, OC(O)R’, cycloalkyl, heterocyclyl, or aryl;
each R is independently H, halo, (CH2)nR’, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)NHR’, NH2, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
any two R groups, taken together with the nitrogen atom to which they are attached, independently form a heterocyclyl; and
each R’ is independently H, C1-6 alkyl, haloalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
Appropriate correction is required. See MPEP § 2173.02.
Claim 31 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method of claim 1, wherein the subject has a mas-related G-protein receptor X2 (MRGPRX2) dependent condition or a mas-related G-protein receptor X2 (MRGPRX2) ortholog dependent condition selected from the group consisting of an autoimmune disorder, an inflammatory disorder, an itch associated condition, a pain associated condition, and a pseudo-allergic reaction.
Appropriate correction is required. See MPEP § 2173.02.
Claim 32 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation(s):
32. The method of claim 31, wherein the itch associated condition is selected from the group consisting of acne, allergic blepharitis, anemia, atopic dermatitis, bullous pemphigoid, burn healing, candidiasis, chicken pox, chronic itch, contact dermatitis, cutaneous amyloidosis, dermatitis herpetiformis, diabetes, a drug allergy, dry skin, dyshidrotic dermatitis, ectopic eczema, end-stage renal failure, eosinophilic fasciitis, epidermolysis bullosa, erythrasma, a food allergy, folliculitis, a fungal skin infection, hemodialysis, hemorrhoids, herpes, an HIV infection, Hodgkin’s disease, hyperthyroidism, an iodinated contrast dye allergy, iron deficiency anemia, kidney disease, leukemia, lichen planus, lichen sclerosis, lymphoma, a malignancy, mastocystosis, multiple myeloma, neurodermatitis, ocular itch, onchocerciasis, Paget’s disease, pediculosis, polycythemia rubra vera, a porphyria, prurigo nodularis, pruritus ani, pseudorabies, psoriasis, rectal prolapse, rosacea, sarcoidosis granulomas, scabies, schistosomiasis, scleroderma, severe stress, stasia dermatitis, swimmer’s itch, thyroid disease, tinea cruris, urticaria, and wound healing.
36. The method of claim 32, wherein the urticaria is chronic urticaria.
Appropriate correction is required. See MPEP § 2173.02.
Claim 33 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation:
The method of claim 32, wherein the itch associated condition is selected from the group consisting of atopic dermatitis, contact dermatitis, dry skin, ectopic eczema, pruritus ani, psoriasis, and urticaria.
Appropriate correction is required. See MPEP § 2173.02.
Claim 34 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation(s):
34. The method of claim 31, wherein the pain associated condition is selected from the group consisting of acute pain, advanced prostate cancer, AIDS-related pain, ankylosing spondylitis, arachnoiditis, arthritis, arthrofibrosis, autoimmune atrophic gastritis, avascular necrosis, back pain, Behcet’s disease, burning mouth syndrome, bursitis, cancer pain, carpal tunnel syndrome, cauda equina syndrome, central pain syndrome, cerebral palsy, cervical stenosis, Charcot-Marie-Tooth (CMT) disease, chronic fatigue syndrome (CFS), chronic pain, collapsed lung (pneumothorax), complex regional pain syndrome (RSD), corneal neuropathic pain, Crohn’s disease, degenerative disc disease, dental pain, Dercum’s disease, dermatomyositis, diabetic peripheral neuropathy (DPN), dystonia, Ehlers-Danlos syndrome (EDS), endometriosis, eosinophilia-myalgia syndrome (EMS), erythromelalgia, fibromyalgia, gout, a headache, herniated disc, hydrocephalus, intercostal neuraligia, interstitial cystitis, irritable bowel syndrome (IBS), juvenile dermatositis (dermatomyositis), knee injury, leg pain, loin pain-haematuria syndrome, lupus, lyme disease, medullary sponge kidney (MSK), meralgia paresthetica, mesothelioma, musculoskeletal pain, myofascial pain, myositis, neck pain, neuropathic pain, occipital neuralgia, osteoarthritis, Paget’s disease, pain syndrome, Parsonage Turner syndrome, pelvic pain, periodontitis pain, peripheral neuropathy, phantom limb pain, pinched nerve, polycystic kidney disease, polymyalgia rhuematica, polymyositis, porphyria, post herniorraphy pain syndrome, postoperative pain, post stroke pain, postherpetic neuralgia (shingles), post-polio syndrome, primary lateral sclerosis, pudendal neuralgia, radiculopathy, Raynaud’s disease, sacroiliac joint dysfunction, sarcoidosis, Scheuemann’s kyphosis disease, sciatica, scoliosis, shingles (herpes zoster), Sjogren’s syndrome, spasmodic torticollis, sphincter of Oddi dysfunction, spinal cerebellum ataxia (SCA), spinal cord injury, spinal stenosis, syringomyelia, a Tarlov cyst, transverse myelitis, trigeminal neuralgia, ulcerative colitis, vascular pain, and vulvodynia.
37. The method of claim 34, wherein the arthritis is psoriatic arthritis or rheumatoid arthritis (RA).
38. The method of claim 34, wherein the cerebral palsy is ataxic cerebral palsy.
39. The method of claim 34, wherein the chronic pain is selected from the group consisting of chronic functional abdominal pain (CFAP), chronic pancreatitis, and chronic pelvic pain syndrome.
40. The method of claim 34, wherein the headache is a migraine headache.
41. The method of claim 34, wherein the postoperative pain is post mastectomy pain or post thoracotomy pain syndrome.
Appropriate correction is required. See MPEP § 2173.02.
Claim 35 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b), the existing recitation should be replaced with the following recitation(s):
35. The method of claim 31, wherein the autoimmune disorder or inflammatory disorder is selected from the group consisting of acne vulgaris, an airway infection, appendicitis, an autoinflammatory disease, bursitis, cardiovascular disease, chronic inflammation, chronic prostatitis, colitis, Crohn’s disease, cutaneous lupus, cystitis, dermatitis, diverticulitis, endometrial pain, glomerulonephritis, graft-versus-host disease, hidradenitis suppurativa, a hypersensitivity, an intestinal disorder, lung inflammation, lupus erythematous, mast cell activation syndrome, multiple sclerosis, otitis, pelvic inflammatory disease, phlebitis, psoriasis, reflex sympathetic dystrophy/complex regional pain syndrome (rsd/crps), reperfusion injury, rhinitis, rheumatoid arthritis, rheumatic fever, rosacea, sarcoidosis, Steven Johnson’s syndrome, tendonitis, toxic epidermal necrolysis, transplant rejection, and vasculitis.
42. The method of claim 35, wherein the airway infection is selected from the group consisting of asthma, chronic obstructive pulmonary disease, reactive airway disorder, sinusitis, and tonsillitis.
43. The method of claim 35, wherein the colitis is ulcerative colitis.
44. The method of claim 35, wherein the cystitis is interstitial cystitis.
45. The method of claim 35, wherein the intestinal disorder is selected from the group consisting of celiac disease, epithelial intestinal disorder, inflammatory bowel disease, and irritable bowel syndrome.
Appropriate correction is required. See MPEP § 2173.02.
Claim Rejections - 35 U.S.C. § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112:
(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.
Method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib)
Claims 1, 5-12, 27, 28 and 31-35 are rejected under 35 U.S.C. § 112(a) as failing to comply with the enablement requirement because the claims contain subject matter, particularly a method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), which was not described in the specification in such a way as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use (perform) the invention commensurate in scope with these claims.
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. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The above factors, regarding the present invention, are summarized as follows:
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(a) Breadth of the claims - the breadth of the claims includes a method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), shown to the right;
(b) Nature of the invention - the nature of the invention is performance of a method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), shown to the right above;
(c) State of the prior art - Nature Reviews: Drug Discovery offers a snapshot of the state of the drug development art. Herein, drug development is stated to follow the widely accepted Ehrlich model which includes: (1) development of a broad synthetic organic chemistry program; (2) subsequent testing of compounds in an appropriate laboratory model for the disease to be treated; and (3) screening of compounds with low toxicity in prospective clinical trials (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205). Similarly, no single drug has been discovered that is effective in treating the myriad of MRGPRX2 or MRGPRX2 ortholog dependent conditions in a subject, including, but not limited to, a pseudo-allergic reaction, chronic itch, an inflammation disorder, a pain disorder, a skin disorder, wound healing, a cardiovascular disease, and/or COPD {See In re Hokum, 226 USPQ 353 (ComrPats 1985)}. Moreover, WO 22/125636 illustrates the synthesis of substituted cyclohexanes having the structure (Ib), and/or methods of use thereof {Lanier, et al. WO 22/125636, 2022};
(d) Level of one of ordinary skill in the art - the artisans performing the inventor’s or joint inventor’s method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience;
(e) Level of predictability in the art - Synthetic organic chemistry is quite unpredictable (See In re Marzocchi and Horton 169 USPQ at 367 ¶3). Similarly, it is well established that [T]he scope of enablement varies inversely with the degree of unpredictability of the factors involved, and physiological activity is generally considered to be an unpredictable factor {See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970)}.
Moreover, the following excerpt is taken from Hackam, et al., with respect to the poor replication of animal research in human clinical trials {Hackam, et al. JAMA, 296(14), 2006, 1731-1732}:
Only about a third of highly cited animal research translated at the level of human randomized trials. This rate of translation is lower than the recently estimated 44% replication rate for highly cited human studies. Nevertheless, we believe these findings have important implications. First, patients and physicians should remain cautious about extrapolating the findings of prominent animal research to the care of human disease. Second, major opportunities for improving study design and methodological quality are available for preclinical research. Finally, poor replication of even high-quality animal studies should be expected by those who conduct clinical research.
(f) Amount of direction provided by the inventor - the invention lacks direction with respect to making and/or using (performing) a method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib);
(g) Existence of working examples - the disclosure is insufficient to allow extrapolation of the limited examples to enable performing the instantly recited method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib).
Similarly, according to the specification, substituted cyclohexanes having the structure (Ib) are capable of treating a variety of MRGPRX2 or MRGPRX2 ortholog dependent conditions in a subject, including, but not limited to, a pseudo-allergic reaction, chronic itch, an inflammation disorder, a pain disorder, a skin disorder, wound healing, a cardiovascular disease, and/or COPD; however, the specification fails to set forth any convincing in vitro and/or in vivo assays corroborating the alleged activity in association with any MRGPRX2 or MRGPRX2 ortholog dependent conditions in a subject, including, but not limited to, a pseudo-allergic reaction, chronic itch, an inflammation disorder, a pain disorder, a skin disorder, wound healing, a cardiovascular disease, and/or COPD. There is insufficient disclosure to reasonably conclude that the method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), as recited, would contribute to treatment of any MRGPRX2 or MRGPRX2 ortholog dependent conditions in a subject, including, but not limited to, a pseudo-allergic reaction, chronic itch, an inflammation disorder, a pain disorder, a skin disorder, wound healing, a cardiovascular disease, and/or COPD. Furthermore, the combination of the instant specification and Lanier, et al. in WO 22/125636, lacks adequate credible evidence to support the assertion that a method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), as recited, would contribute to the prophylaxis of any MRGPRX2 or MRGPRX2 ortholog dependent conditions in a subject, including, but not limited to, a pseudo-allergic reaction, chronic itch, an inflammation disorder, a pain disorder, a skin disorder, wound healing, a cardiovascular disease, and/or COPD, since the inventor or joint inventor has neither provided convincing data for any subject population, nor indicated any art recognized correlation between the disclosed data and the breadth of the claims.
Within the specification, [A]t least one specific operative embodiment or example of the invention must be set forth. The example(s) and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula. See MPEP § 608.01(p) and MPEP § 2173.05.
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(h) Quantity of experimentation needed to make and/or use (perform) the invention based on the content of the disclosure - predicting whether a recited compound is in fact one that produces a desired physiological effect at a therapeutic concentration and with useful kinetics, is filled with experimental uncertainty, and without proper guidance, would involve a substantial amount of experimentation (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205-213). Furthermore, it is unclear, based on the guidance provided by the specification, whether a substituted cyclohexane having the structure (Ib), such as N-((1s,4s)-4-((4-cyano-3-(trifluoromethyl)phenyl)amino)cyclohexyl)-1H-indole-4-carboxamide, shown to the left above, possesses utility as a therapeutic agent, useful in a method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib). Thus, one of ordinary skill in the art, at the time this invention was made, would have an unreasonable expectation of success and undue experimentation in transferring the in vitro and/or in vivo method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), wherein the MRGPRX2 or MRGPRX2 ortholog dependent condition in a subject, includes, but is not limited to, a pseudo-allergic reaction, chronic itch, an inflammation disorder, a pain disorder, a skin disorder, wound healing, a cardiovascular disease, and/or COPD, to any subject population.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use (perform) the full scope of the claimed invention without undue experimentation. {See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)}.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. (See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404). These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for making and/or using (performing) a method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), is clearly justified.
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim Rejections - 35 U.S.C. § 112(b)
The following is a quotation of the second paragraph of 35 U.S.C. § 112:
(b) CONCLUSION. The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or joint inventor regards as the invention.
Claims 1, 5-12, 27 and 28 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that claim 1 is a reach-through claim. The claim attempts to obtain protection for subject matter that is prophetic and/or has yet to be invented. Similarly, the metes and bounds of the treatable MRGPRX2 or MRGPRX2 ortholog dependent conditions in a subject are not defined by the claim, the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. Likewise, the specification, on page 1, uses open language, such as including, to define treatable MRGPRX2 or MRGPRX2 ortholog dependent conditions in a subject as a pseudo-allergic reaction, chronic itch, an inflammation disorder, a pain disorder, a skin disorder, wound healing, a cardiovascular disease, and/or COPD; however, neither the specification, nor the claim, explicitly limits the invention to any specifically disclosed or recited embodiments, including, but not limited to, a pseudo-allergic reaction, chronic itch, an inflammation disorder, a pain disorder, a skin disorder, wound healing, a cardiovascular disease, and/or COPD. Consequently, the method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib) has been rendered indefinite by the use of the reach-through protocol.
Moreover, the inventor or joint inventor should further note that [C]laims which depend from indefinite claims are also indefinite. {See Ex parte Cordova, 10 USPQ 2d 1949, 1952 (PTO Bd. App. 1989)}.
The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim 27 is further rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that a broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c), MPEP § 2173.05(h), and/or Eli Lilly & Co. v. Teva Parenteral Meds., 845 F.3d 1357, 1371, 121 USPQ2d 1277, 1287 (Fed. Cir. 2017).
Similarly, the inventor or joint inventor should further note that claim 27 recites the broad limitation, or a stereoisomer thereof, and the claim recites cis or (S,S), respectively, which is the narrower statement of the limitation.
Likewise, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), pertaining to where broad language is followed by such as and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and consequently, not required, or (b) a required feature of the claim.
Moreover, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim 32 is further rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that a broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c), MPEP § 2173.05(h), and/or Eli Lilly & Co. v. Teva Parenteral Meds., 845 F.3d 1357, 1371, 121 USPQ2d 1277, 1287 (Fed. Cir. 2017).
Similarly, the inventor or joint inventor should further note that claim 32 recites the broad limitation, urticaria, and the claim recites chronic urticaria, which is the narrower statement of the limitation.
Likewise, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), pertaining to where broad language is followed by such as and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and consequently, not required, or (b) a required feature of the claim.
Moreover, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim 33 is further rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that claim 33 recites the limitation, The method of claim 32, wherein the itch associated condition is… pruritis… or eczema, in lines 1-2 of the claim. There is insufficient antecedent basis, in claim 32, for this limitation, with respect to the method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition in a subject in need thereof. According to claim 32, neither pruritis, nor eczema, is recited, with respect to the method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition in a subject in need thereof.
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim 34 is further rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that a broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c), MPEP § 2173.05(h), and/or Eli Lilly & Co. v. Teva Parenteral Meds., 845 F.3d 1357, 1371, 121 USPQ2d 1277, 1287 (Fed. Cir. 2017).
Similarly, the inventor or joint inventor should further note that claim 34 recites the broad limitations, (1) arthritis; (2) cerebral palsy; (3) chronic pain; (4) headache; and (5) postoperative pain, respectively, and the claim recites (1) psoriatic arthritis and rheumatoid arthritis (RA); (2) ataxic cerebral palsy; (3) chronic functional abdominal pain (CFAP), chronic pancreatitis, and chronic pelvic pain syndrome; (4) migraine; and (5) post mastectomy and post thoracotomy pain syndrome, respectively, which are the narrower statements of the limitations.
Likewise, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), pertaining to where broad language is followed by such as and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and consequently, not required, or (b) a required feature of the claim.
Moreover, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim 35 is further rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention.
The inventor or joint inventor should note that a broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c), MPEP § 2173.05(h), and/or Eli Lilly & Co. v. Teva Parenteral Meds., 845 F.3d 1357, 1371, 121 USPQ2d 1277, 1287 (Fed. Cir. 2017).
Similarly, the inventor or joint inventor should further note that claim 35 recites the broad limitations, (1) airway infection; (2) colitis; (3) cystitis; and (4) intestinal disorder, respectively, and the claim recites (1) asthma, chronic obstructive pulmonary disease, reactive airway disorder, sinusitis, and tonsillitis; (2) ulcerative colitis; (3) interstitial cystitis; and (4) celiac disease, epithelial intestinal disorder, inflammatory bowel disease, and irritable bowel syndrome, respectively, which are the narrower statements of the limitations.
Likewise, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), pertaining to where broad language is followed by such as and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and consequently, not required, or (b) a required feature of the claim.
Moreover, the inventor or joint inventor should further note the explanation given by the Board of Patent Appeals and Interferences in the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this rejection.
Claim Rejections - 35 U.S.C. § 112(d)
The following is a quotation of the fourth paragraph of 35 U.S.C. § 112:
(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.
Claim 28 is rejected under 35 U.S.C. § 112(d) 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.
The inventor or joint inventor should note that claim 28 is rejected under 35 U.S.C. § 112(d) because the recitation of an additional process performed on a compound administered within a method from which the claim depends, must result in a patentably distinct procedural step in the recited method, in order to be further limiting. In the instant dependent claim, the substituted cyclohexane having the structure (Ib) administered within the method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition in a subject, as recited in claim 1, is administered as a pharmaceutical composition. Consequently, since the additional process performed on the substituted cyclohexane having the structure (Ib) administered within the method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition in a subject, as recited in claim 1, whereby the substituted cyclohexane having the structure (Ib) is administered as a pharmaceutical composition, (1) fails to result in a further patentably distinct procedural step in the method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), as recited in claim 1, and/or (2) fails to include all the limitations of the method of treating a MRGPRX2 or a MRGPRX2 ortholog dependent condition by administering to a subject in need thereof an effective amount of a substituted cyclohexane having the structure (Ib), as recited in claim 1, it is not given patentable weight and thus, renders the instant dependent claim improperly dependent under 35 U.S.C. § 112(d). {See MPEP § 2111.02; and 37 CFR 1.75(c)}.
Similarly, the inventor or joint inventor should further note that the U.S. Court of Appeals for the Federal Circuit indicated that although the requirements of 35 U.S.C. § 112(d) are related to matters of form, non-compliance with 35 U.S.C. § 112(d) renders the claim unpatentable just as non-compliance with other subsections of 35 U.S.C. § 112 would. {See Pfizer, Inc. v. Ranbaxy Labs., Ltd., 457 F.3d 1284, 1291-92 (Fed. Cir. 2006)}.
Moreover, the inventor or joint inventor should further note that if a dependent claim does not comply with the requirements of 35 U.S.C. § 112(d) the dependent claim should be rejected under 35 U.S.C. § 112(d) as unpatentable rather than objecting to the claim. {See also MPEP § 608.01(n), Section III, Infringement Test for dependent claims}.
The examiner suggests the inventor or joint inventor (1) cancel the dependent claim, (2) amend the dependent claim to place the dependent claim in proper dependent form, (3) rewrite the dependent claim in independent form, particularly as stated in the section above entitled Claim Objections, or (4) present a sufficient showing that the dependent claim complies with the statutory requirements, to overcome this rejection.
Allowable Subject Matter
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS M. WILLIS, whose telephone number is 571-270-5757. The examiner may normally be reached on Monday thru Thursday from 8:00-6:00 EST. The examiner is also available on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Jeffrey Murray, may be reached on 571-272-9023. The fax phone number for the organization where this invention or proceeding is assigned is 571-273-8300.
Information regarding the status of an invention may be obtained from Patent Center. For more information about Patent Center, see https://www.uspto.gov/patents/apply/patent-center. Should you have questions on access to Patent Center, contact the Patent Electronic Business Center (PEBC) at 866-217-9197 (toll-free) or ebc@uspto.gov.
/DOUGLAS M WILLIS/
Primary Examiner, Art Unit 1624