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 .
Information Disclosure Statement
The information disclosure statement submitted on 09/15/2023, 01/27/2025, and 04/03/2026 are in compliance with the provisions of 37 CFR 1.97. However, The International Search Report for PCT/US2022/071209 on IDS 09/15/2023 was not placed in the application contents and has been lined through. Accordingly, the information disclosure is being considered by the examiner, except where lined through.
Drawings
The drawings are objected to because Figs. 1A and 1B have axis labels that are difficult to read and Fig. 5 refers to improving or worsening patient condition by either green or purple bars, but in grayscale the colors look the same. Color drawings are not required; however, the grayscale must be adjusted to distinguish between improvement or worsening of symptoms in Figure 5.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 4 is objected to because of the minor informality: “strescopin” should be “stresscopin”.
Claims 10 and 16 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Interpretation
The “threshold concentration of stimulation (CT)” is being interpreted as the plasma concentration of a composition at which healthy patients have a significant change in a physiological parameter, such as a change in heart rate (see instant specification [0006], [0060], [0061], Fig. 1A). Thus, CT is not necessarily where the composition becomes therapeutically effective, but rather the point at which a physiological change occurs. Furthermore, the CT as determined from healthy controls is applied subjects with CRFR2 maladaptation (instant specification, first two lines of [0060]).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4 and 7 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 4 is rejected as indefinite for reciting exemplary species “UCN1, UCN2, or UNC3” in parenthesis following the recitation of the urocortin peptide genus. It is unclear whether a prior art reference teaching one species would meet the claim limitation or if prior art reference must teach the entire genus. Therefore, the metes and bounds of the claim are unclear. For the purposes of examination, it will be interpreted as the claim only requiring a single species of urocortin peptide.
Claim 7 is rejected as indefinite because “the plasma concentration” lacks antecedent basis. For the purposes of claim interpretation, this claim will be interpreted as: “…wherein CT38s is administered to maintain a CT of CT38s of 0.25ng/mL…”
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 17 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 17 broadens the claim from which it depends, claim 11, by reciting “…wherein the CRFR2 agonist is one or more of…” (emphasis added). Claim 11 recites administering “a CRFR2 agonist” (emphasis added). Therefore, Claim 17 broadens the scope by reciting that more than one CFRF2 agonist can be administered.
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 § 112(a)
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 1-8, 10-14, 16-20 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 encephalomyelitis/chronic fatigue syndrome, does not reasonably provide enablement for the genus of all functional somatic syndromes or corticotropin-releasing factor receptor 2 (CRFR2) maladaptations, nor for post-acute sequelae of SARS-CoV-2 infection. 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.
To assess whether any necessary experimentation required by the specification is “reasonable” or is “undue” the following Wands factors may be considered:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims:
Claims 1-8, 11-13, 16-20 recite a method of treating a CRFR2 maladaptation by administering a CRFR2 agonist in an amount to maintain the plasma concentration of the CRFR2 agonist in the subject below a CT of CRFR2 agonist. Maladaptation is not defined in the specification; under broadest reasonable interpretation, maladaptation includes any change in CRFR2 expression or signaling.
Claims 10 and 16 further limit that the maladaptation is post-acute sequelae of SARS-CoV-2.
Claim 14 further limits that the maladaptation is a functional somatic syndrome, which itself is broad genus of conditions.
Accordingly, the claims are extremely broad, encompassing a vast number of conditions that differ in their onset and localization in the body.
The state of the art and level of predictability:
The state of the art teaches that the genus of “functional somatic syndromes” is a group of conditions defined by shared symptoms that are medically unexplained (Mayou et al., Functional Somatic Symptoms and Syndromes, 2002, BMJ, Clinical Review, 325:265-268; specifically see “abstract”, see instant PTO-892). In other words, functional somatic syndromes, and therefore the conditions encompassed by the broader genus of CRFR2 maladaptations, do not necessarily have the same mechanistic cause, namely changes to CRFR2 expression or signaling.
Furthermore, even for irritable bowel syndrome (IBS), a functional somatic syndrome for which a nexus with disruption in corticotropin-releasing factor signaling has been proposed (Nozu, Corticotropin-releasing factor receptor type 1 and type 2 interaction in irritable bowel syndrome, 2015, J Gastroenterol, pg. 823 “A balance theory”; see instant PTO-892), the state of art is not enabling for treating IBS via administration of CRFR2 agonists below a CT threshold. For example, Nozu suggests CRF2 agonists to counteract CRF1 overactivity (Nozu, Fig. 2C), but there is no evidence to suggest that a dose of CFRF2 agonist with a plasma concentration below a CT threshold would be sufficient to counteract the CRF1 overactivity characteristic of IBS.
Regarding treating post-acute sequelae of SARS-CoV-2 (also called long Covid), at the time of filing, the mechanistic cause of the condition was unknown. For example, Crook et al. (Long covid—mechanisms, risk factors, and management, July 2021, State of the Art Review, pgs. 1-18; see instant PTO-892) teaches that “It is likely that a range of central, peripheral, and psychological factors play a role in the development of post-covid-19 fatigue,” (pg. 5, right side, last paragraph) and also suggests resistance to cerebrospinal fluid drainage (pg. 6, left side, first paragraph) as a potential mechanistic path of long Covid. Thus, even after the filing date, the cause of post-acute sequelae of SARS-CoV-2 was not ascertained such that one of ordinary skill in the art would have a reasonable expectation of success administering a CRFR2 agonist below a CT threshold to treat it.
The state of the art teaches the administration of a CRFR2 agonist below a CT threshold does treat heart failure (Gengo et al. US20110105397A1; [0015],[0221],[0228], [0137]; see instant PTO-892) and chronic fatigue syndrome Bateman (Clinical Trials.gov: "Clinical Trial to Investigate CT38 in the treatment of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (InTiME), May 12 2020 National Library of Medicine, pg. 6 , “Outcome Measures”; hereafter Bateman I, see instant PTO-892).
Altogether, the state of the art provides limited evidence that the full scope of CRFR2 maladaptations and functional somatic syndromes, nor long Covid, have a CRFR2 maladaptation such that they would benefit from CRFR2 agonist administration at a dose that maintains the plasma concentration of the agonist below a CT.
The amount of direction provided by the inventor and the existence of working examples:
The specification teaches a single clinical study directed toward treating ME/CFS patients with CT38s (pg. 34-46). There is no evidence in the specification that patients with post-acute sequelae of SARS-CoV-2, or any of the other conditions encompassed by CRFR2 maladaptation, exhibit changes in CRFR2 expression or signaling.
There is no discussion in the specification of how one of ordinary skill would have a reasonable expectation of success administering a dosage of CRFR2 agonist below a CT threshold, which, as described above, is simply the threshold at which healthy individuals have a physiological response, not necessarily where the agonist becomes therapeutically effective.
Thus, the specification does not address the lack of prior art linking functional somatic syndromes or long Covid to CRFR2 maladaptation nor how such a low dose of agonist would be expected to treat the full scope of all these conditions.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
Because the disclosure only teaches working examples directed toward treating CFS, one of ordinary skill would have to determine which conditions demonstrate CRFR2 maladaptation, such that it would benefit from administration of a CRFR2 agonist administration below a CT in order to use the claimed invention.
However, this would require a significant amount of experimentation. Johnson (Cortene to Move Forward on New Drug for Chronic Fatigue Syndrom (ME/CFS), 2019, Health Rising, pgs. 1-64; see instant IDS 01/27/2025) teaches that “it’s impossible to measure CRF2 levels inside a live brain” (pg. 2, third paragraph). Determining which conditions would benefit from the claimed method is further complicated by the fact that not all functional somatic syndromes have a reliable animal model. For example, Bateman (Clinical Trial Protocol Pilot Phase 1/2 , Open-Label, Clinical Trial to Investigate CT38 in the Treatment of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (InTiME), 2018, ClinicalTrials.gov, pgs. 1-24; see instant PTO-892; hereafter Bateman II) teaches that ME/CFS has no animal model (pg. 8, last paragraph). Thus, determining which patient populations potentially could benefit from a CRFR2 agonist, let alone at a plasma concentration below the CT threshold, has significant constraints that go beyond routine experimentation to identify a target a patient population.
Conclusion:
The specification is not enabling for treating the full scope of CRFR2 maladaptations or functional somatic syndromes, nor for treating post-acute sequelae of SARS-CoV-2, by administering the subject with a CRFR2 agonist at a plasma concentration below a CT threshold; however, based on the state of the art and the disclosure in the instant specification, the specification is enabling for treating heart failure and chronic fatigue syndrome by administering the subject with a CRFR2 agonist at a plasma concentration below a CT threshold.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-9, 11-15, and 17-20 is/are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Bateman (Clinical Trials.gov: "Clinical Trial to Investigate CT38 in the treatment of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (InTiME), May 12 2020 National Library of Medicine, pgs. 1-17; hereafter Bateman I, see instant PTO-892), as evidenced by Bateman (Clinical Trial Protocol Pilot Phase 1/2 , Open-Label, Clinical Trial to Investigate CT38 in the Treatment of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (InTiME), 2018, ClinicalTrials.gov, pgs. 1-24; hereafter Bateman II; see instant PTO-892).
Regarding claims 1, 4, 5, 9, 11, 14, 15, 17 and 18 Bateman I teaches controlled release via subcutaneous infusion (pg. 3, “Participant Flow” Table) of CT38 (pg. 1, last two lines) to a subject (pg. 3, “Participant Flow” Table) to treat a functional somatic syndrome called chronic fatigue syndrome (pg. 1, “Conditions”). As evidenced by Bateman II, the CT38 version administered is CT38s (pg. 4, “Study Agent”, last two lines).
The instant specification teaches that administering CT38s ([0098] lines 1-2) at 0.01 μg/kg/hour ([00102] last three lines; Table 2) to humans ([0099]; [00103]) via subcutaneous infusion ([0095], line two) (i.e. the D01 cohort) results in a plasma concentration below 0.25 ng/ml ([00107]), an area under the plasma concentration-time curve (AUC) of 1.02-1.29 ng*h/ml (pg. 45, Table 7, Patient ID Nos. 38 and 45), and persistent improvement of symptoms after the last dose ([00107] first 6 lines; Fig. 4; Figs. 6A and B), as demonstrated by a decrease in Total Daily Symptom Score (TDSS) over a 28 day period (Fig. 4).
Regarding claims 8 and 19, Bateman I teaches administration of CT38s at 0.01 μg/kg/hour to humans via subcutaneous infusion (pg. 3, “Participant Flow” table). Regarding claim 12, Bateman I further teaches a decrease in TDSS over a 28 day period since the last dose (pgs. 6-7, “Outcome Measures” Table) which measures the score of symptoms such as fatigue, muscle/joint pain, sleep problems, cognitive problems, orthostatic intolerance, body temperature perceptions, flu-like symptoms, headaches or insensitivities, shortness of breath, gastrointestinal problems, urogenital problems, anxiety and depression (last two lines of pg. 6, first paragraph of pg. 7). Therefore, regarding claims 2, 3, 6, 7, and 11- 13, it would naturally follow that the administration of CT38s taught by Bateman I, which uses the same administration method, subject, dose and rate as the instant specification, would also lead to a plasma concentration below 0.25 ng/ml, persistent improvement in symptoms following cessation of CT38s administration, and an AUC of about 5 ng*h/ml.
Claim(s) 1, 2, 4, 11, and 17 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gengo et al. US20110105397A1 (see instant PTO-892).
Regarding claims 1, 4, 11, and 17, Gengo et al. teaches a method of treating heart failure by administering a CRFR2 agonist, human stresscopin (h-SCP) ([0009]) to a subject (Fig. 4), where the plasma level of the peptide is maintained at a level that increases cardiac performance without significant increase in heart rate or a significant decrease in blood pressure [0015], [0221], [0228], [0237]. Based on the claim interpretation described above, this reads on maintenance of plasma concentration below a CT. Furthermore, heart failure is a CHRH maladaptation because it is associated with corticotrophin releasing hormone receptor type 2 (CRHR2) (i.e. CRFR2 recited in the instant claims) activity [0013] that is detrimental (i.e. results in heart failure). Regarding claims 2 and 11, Gengo et al. teaches persistent improvement in cardiac performance (Figs. 11A and B). Regarding claim 11, Gengo et al. further teaches that the composition administered is preferably administered via a parenteral route [0020] such as subcutaneous infusion [0158]; the instant specification teaches subcutaneous infusion is a type of controlled-release (last four lines of [0033]).
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.
Claim(s) 5-8, 18-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gengo et al., as applied to claims 1 and 11 above, in view of Bateman (Clinical Trial Protocol Pilot Phase 1/2 , Open-Label, Clinical Trial to Investigate CT38 in the Treatment of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (InTiME), 2018, ClinicalTrials.gov, pgs. 1-24; see instant PTO-892) (hereafter Bateman II) and in further view of Hossain Mithu (Advanced Methodologies for Pharmaceutical Salt Synthesis, Jan 2021, Crystal Growth and Design, pgs. 1358-1374; see instant PTO-892).
Gengo, as applied to claims 1 and 11, teaches a method of treating heart failure by administering h-SCP, which is a CRFR2 agonist, to a subject via subcutaneous infusion such as subcutaneous infusion in a plasma concentration below a CT to induce persistent improvement in a symptom.
Gengo et al. further teaches that the stresscopin-like peptide administered to treat heart failure is selective for CRFR2 [0091]. Gengo et al. further teaches that the area under the plasma concentration-time curve (AUC) varies (Table 25). Gengo et al. further teaches that plasma concentration is maintained between 0.1ng/mL to 7.2ng/mL. Regarding claims 8 and 19, Gengo et al. further teaches a dosing rate of h-SCP of 1 ng/kg min (which is equivalent to 0.001 μg/kg/hour).
Gengo et al. does not teach i) administration of CT38s to achieve an AUC of about 5 ng*h/mL (instant claim 6), ii) maintaining the plasma concentration of CT38s below about 0.25ng/ml to induce persistent improvement of a symptom associated with CRFR2 maladaptation (instant claim 7), iii) a dosing rate of CT38s of at least 0.0001 μg/kg/hour (instant claim 8) or iv) a controlled-release dose of CT38s administered at a rate not exceeding about 0.03 μg/kg/hour (instant claim 19).
Bateman II teaches that CT38 has little to no off target binding (pg. 8, 1.1.2.3; first three lines). Bateman II teaches that CT38s is the acetate salt version of CT38 (pg. 7, 1.1.2.1, first line) and is used for subcutaneous administration (pg. 8, 1.1.2.3 “Safety Pharmacology and Toxicology”; pg. 4, “Study Agent”, last two lines).
Hossain Mithu teaches that “pharmaceutical salt formation is the most preferred and effective method to enhance the physicochemical properties of an active pharmaceutical ingredient” (abstract) and is regularly used to improve solubility of an active pharmaceutical ingredient (pg. 2, “Pharmaceutical salts to improve solubility”, first line).
It would be obvious to substitute one selective CRFR2 agonist, h-SCP, in the method of treating heart failure by administering h-SCP below a CT via a subcutaneous infusion, as taught by Gengo et al., with another CRFR2 agonist, CT38s, as taught by Bateman II, to arrive at a method of treating heart failure by administering CT38s to a subject via a subcutaneous infusion to maintain plasma concentration below a CT. One would have been motivated to substitute the CRFR2 agonist from h-SCP to CT38s because CT38 has no known off-target activity, as taught by Bateman II, and the salt formation (i.e. CT38s) enhances solubility for subcutaneous infusion, as taught by Hossain Mithu. There would be a reasonable expectation of success treating heart failure by administering CT38s below a CT, because it is a functionally equivalent CRFR2 agonist.
Regarding claims instant claims 6-8 and 19, through routine optimization, it would be obvious to modify the dosing regimen, namely the dosing rate, plasma concentration, and AUC of CT38s of modified Gengo et al., Bateman II, and Hossain Mithuto arrive at the claimed dosing regimen: i) administration of CT38s to achieve an AUC of about 5 ng*h/mL (instant claim 6), ii) maintenance of the plasma concentration of CT38s below about 0.25ng/ml to induce persistent improvement of a symptom associated with CRFR2 maladaptation (instant claim 7), iii) dosing CT38s at a rate of at least 0.0001 μg/kg/hour (instant claim 8) and iv) controlled-release of CT38s administered at a rate not exceeding about 0.03 μg/kg/hour (instant claim 19). Regarding claims 6, 8 and 19, Gengo et al. teaches that the dosing rate and AUC are a result effective variables because various infusion rates and types were used (pgs. 31- 33, Tables 21-25), which also subsequently impacts the AUC. Through routine optimization, it would be obvious to modify the dosing rate and AUC to arrive at the claimed parameters of a dosing rate for CT38s of at least 0.0001 μg/kg/hour, not exceeding 0.03 μg/kg/hour. Furthermore, the dosing rate of SCP of 0.001 μg/kg/hour taught by Gengo et al. reads on this range; in other words, Gengo et al. teaches the claimed dosing rate but for a different CRFR2 agonist, providing more support that it would be obvious to arrive at the claimed dosing rate when optimizing dosing rate for a CRFR2 agonist.
Regarding claim 7, it would be obvious to one of ordinary skill in the art that the CT will change based on a variety of variables including the CRFR2 agonist used, the species of subject being treated, and administration type. Indeed [0068] of the instant specification admits that even for the same patient population and drug administered, the threshold can change; therefore, CT is a result effective variable. Through routine optimization, it would be obvious to modify the CT to arrive at maintaining a plasma concentration of CT38s below 0.25 ng/mL to induce persistent improvement in at least one symptom associated with maladaptation.
MPEP §§ 2144.05 states: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages," (see In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382). Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," (See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Claim(s) 9 and 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gengo et al., as applied to claims 1 and 11 above, in further view of Johnson (Cortene to Move Forward on New Drug for Chronic Fatigue Syndrome (ME/CFS), 2019, Health Rising, pgs. 1-64; see instant IDS 01/27/2025) and Castro-Marrero (Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome, 2017, British Journal of Pharmacology, pgs. 1-25), as evidenced by Bateman II.
Gengo, as applied to claims 1 and 11, teaches a method of treating heart failure by administering the h-SCP, which is a CRFR2 agonist, to a subject via subcutaneous infusion in a plasma concentration below a CT to induce persistent improvement in a symptom.
Gengo et al. further suggests that the administration of a stresscopin-like peptide could be used to treat other conditions mediated by CRFR2 activity beyond just heart failure [0063].
Gengo et al. does not teach a method of treating a functional somatic syndrome, specifically chronic fatigue syndrome.
Johnson suggests that patients with CFS exhibit over expression of CRF2 (i.e. CRFR2 in the instant claims) (pg. 2, first paragraph). Johnson teaches administration of CT38 to treat chronic fatigue syndrome (CFS) (pg. 2, “The Study”). As evidenced by Bateman II, CT38 is a CRF2 agonist (pg. 7, 1.1.2. “Investigational Agent”; first paragraph). Johnson also teaches that CFS patients “reacted to the drug at far lower doses” (pg. 3, third sentence of first paragraph) than healthy controls, putatively because of increased CRF2 (i.e. CRFR2 in the instant claims) activity in CFS subjects (pg. 2, first paragraph). Lastly, Johnson teaches that limited doses of CT38 produce persistent improvement in symptoms (pg. 3, first paragraph). In other words, Johnson teaches that CFS patients are a patient population that benefits from low dosing of a CRFR2 agonist in theory because of overactivity of CRFR2.
Castro-Marrero teaches that at the time of instant filing, there was no FDA-approved treatments for CFS (pg. 3, left side, second paragraph); most treatment options focus on managing symptoms (pg. 3, left side, first five lines of second paragraph) rather than treating underlying physiology (pg. 3, right side, 8 lines from bottom). Table 1 of Castro-Marrero (pgs. 9-12) demonstrates that the range of therapies attempted to treat CFS but with limited success.
It would be obvious to use the method of treating heart failure by administering the CRFR2 agonist h-SCP below a CT via a subcutaneous infusion, as taught by Gengo et al, to treat chronic fatigue syndrome (CFS), as taught Johnson, in order to arrive at a method of treating CFS by administering h-SCP via a subcutaneous infusion to maintain a plasma concentration of h-SCP below a CT of CRFR2 agonist and induce persistent improvement in at least one symptom of CFS. One of ordinary skill would be motivated to use the Gengo method to treat chronic fatigue syndrome to meet the unmet need of CFS treatment, as demonstrated by Castro-Marrero. There would be a reasonable expectation of success because i) Gengo teaches heart failure patients benefit from low-dosing of a CRFR2 agonist to treat maladaptive CRFR2 activity, ii) Johnson suggests the CFS patients also exhibit CRFR2 overactivity, and iii) Johnson teaches that CFS patients also respond to low doses of a CRFR2 agonist. In other words, using h-SCP to treat another patient population (i.e. CFS patients) that is also characterized by CRFR2 overactivity would have a reasonable expectation of success and this is further supported by Johnson’s teachings that this patient population already responded to a CRFR2 agonist at low doses.
Conclusion
No claims allowed.
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/MICHELLE CALLAHAN BUCCINI/Examiner, Art Unit 1675
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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