DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claims 1-2, 9, 11, 13, 17, 19, 27, 30-34, 37, 40-41, 47, 54, 56 and 58 filed February 03, 2023 are currently pending.
Election/Restrictions
Applicant’s election without traverse of Group (I) claims 1, 2, 9, 11, 13, 17, 19, 27, 30-34, 41, 47, 54, 56 and 58 in the reply filed on 07/01/2025 is acknowledged. Secondly, Applicant’s election without traverse of a patient comprising chronic non-cancer pain as the disease or disorder, hydrocodone as the species of opioid analgesic and a patient not suffering from an opioid induced bowel disorder are acknowledged.
Claims 11, 17, 30-31, 37, 40, 54 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species of patient population, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/01/2025.
Priority
Acknowledgement is made of the continuation of PCT/EP2021/061453 filed 04/30/2021 which claims priority to U.S. Provisional Application 63019301 filed 05/02/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04/04/2025, 04/16/2025 and 07/01/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112-Paragraph 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.
Claim 58 is 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 58 is directed to the method of claim 1 wherein the method further comprises determining whether a subject has, and/or has previously had, an increased risk of death based on the presence of various risk factors, optionally, as listed under Table 3.
MPEP 2173.05 (s) states that where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). In the present case, Table 3 lists seven distinct cardiovascular risk factors including hypertension, hyperlipidemia, hypercholesterolemia, diabetes mellitus, myocardial infarction, stroke, angina.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 1-2, 9, 13, 19, 27, 32-34, 41, 47, and 58 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Moss (US2017/0202832 published 07/20/2017).
Claim 1 is directed to a method of reducing mortality risk in a subject suffering from an underlying disease or condition, comprising administering to the subject an effective amount of a composition comprising methylnaltrexone (MNTX), or a salt thereof. Claim 34 is directed to a method of reducing mortality risk in a subject receiving opioid therapy comprising administering to the subject one or more methylnaltrexone pharmaceutical compositions selected from the group consisting of a methylnaltrexone pharmaceutical composition for oral administration, a methylnaltrexone ion pair pharmaceutical composition, and a methylnaltrexone pharmaceutical composition for subcutaneous administration, optionally, wherein the subject has an underlying disease or condition, optionally, selected from the group consisting of an advanced illness, cancer, a chronic non-cancer pain, postoperative ileus, and recovery from orthopedic surgery, and combinations thereof.
Given the broadest reasonable interpretation of the claims, neither claim 1 nor 34 excludes wherein the subject is suffering from cancer and comprises opioid induced constipation due to treatment with chemotherapy and opioid therapy.
Moss (US2017/0202832 published 07/20/2017) teaches the method of treating neoplastic patients with opioid induced constipation comprising administering a therapeutically effective amount of methylnaltrexone. As shown in Figures 2-3, 7-9, and 12-25, cancer patients treated with chemotherapy and opioid therapy and developed opioid induced constipation were further treated with methylnaltrexone, wherein an increase in overall survival was seen compared to control patients ([0189]-[0205], [0363]-[0384], [0395]). As shown in Figures 9-10, said methylnaltrexone responsive patients comprised an increase in lifespan of at least 121 days (3-4 months) compared to non-responders (58 days), which reads on the limitation of claim 33 ([0400]-0401]).
Regarding claim 9, as shown in Table 3, treatment of patients under 60 years of age with the methylnaltrexone therapeutic regimen is taught by Moss ([0392]-[0393]).
Regarding claim 19, Moss teaches oral administration of methylnaltrexone in a dose of 150 mg, wherein the methylnaltrexone is administered as a tablet ([0034]-[0035]).
Regarding claim 27 and 41, Moss teaches that the cancer patient is administered at least one opioid, such as 20-200 mg of oral morphine equivalents for at least 1-30 days prior to the administration of the therapeutically effective amount of methylnaltrexone [0018]-[0021], [0042]-[0043], [0331]). Regarding claim 32, administration of methylnaltrexone bromide ion pair is taught by Moss ([0217], [0249]-[0251]).
Regarding claim 58, Moss teaches that the disclosed methodology is efficacious for subjects who are receiving opioids and reduce complications from chronic constipation such as myocardial infarction ([0314]). As shown in Table 3 of the present specification, myocardial infarction is one of seven risk factors associated with the risk of death.
Claim(s) 1-2, 9, 13, 19, 27, 32-34, 41, and 47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Webster (Journal of Pain Research Vol. 11 pages 1503-1510. Published 2018).
Claim 1 is directed to a method of reducing mortality risk in a subject suffering from an underlying disease or condition, comprising administering to the subject an effective amount of a composition comprising methylnaltrexone (MNTX), or a salt thereof. Claim 34 is directed to a method of reducing mortality risk in a subject receiving opioid therapy comprising administering to the subject one or more methylnaltrexone pharmaceutical compositions selected from the group consisting of a methylnaltrexone pharmaceutical composition for oral administration, a methylnaltrexone ion pair pharmaceutical composition, and a methylnaltrexone pharmaceutical composition for subcutaneous administration, optionally, wherein the subject has an underlying disease or condition, optionally, selected from the group consisting of an advanced illness, cancer, a chronic non-cancer pain, postoperative ileus, and recovery from orthopedic surgery, and combinations thereof.
Given the broadest reasonable interpretation of claims 1 and claims 34, claims 1 and 34 do not exclude wherein the subject is suffering from chronic non-cancerous pain and comprises opioid induced constipation.
Webster (Journal of Pain Research Vol. 11 pages 1503-1510. Published 2018) Webster teaches that opioid induced constipation affects between 40% and 95% of patients on long term opioid therapy (page 1504 left col.). Webster teaches the method of treating a patient comprising chronic non-cancerous pain in a subject being treated with > 50 mg oral morphine equivalent dose comprising administering a therapeutically effective amount of methylnaltrexone (abstract, page 1504 right col. through page 1505 left col.).
Regarding claim 9, patients >18 years with a median age of 51 years were treated with the disclosed methylnaltrexone therapeutic regimen (page 1504 right col. Table 1). Regarding claim 19, oral administration of methylnaltrexone in 150 mg tablet form in a dose of one, two or three tablets per day is taught by Webster (page 1505 left-right col.).
Mean pain intensity scores remained stable with the combination of methylnaltrexone and morphine regimen to the chronic non-cancer pain patient (Table 2). Webster teaches that said regimen results in significant dos-related improvement of opioid induced constipation without compromising analgesia by the opioid therapeutic (page 1508, right col).
Regarding claim 32, Webster teaches that the present analysis is of a Phase III multicenter, randomized, double-blinded, placebo-controlled clinical trial (NCT01186770) (page 1504 right col.). As evidenced by NCT0186770, the clinical trial administered methylnaltrexone as Relistor (page 6). As evidenced by CAS REGISTRY DATABASE Relistor product page, Relistor is the ion pair N-methylnaltrexone bromide.
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It is noted that Webster does not specifically teach wherein the chronic non-cancer pain patient receiving 50 mg oral morphine and either 150mg, 300 mg or 450 mg of methylnaltrexone results in the extension of the lifespan of said patient by at least 30 days (claim 33). Although said property is not explicitly described in the prior art methodology of Webster, the composition (150 mg, 300 mg or alternatively, 450 mg of oral methylnaltrexone and 50 mg oral morphine) and the patient population (chronic non-cancerous pain patient) are identical to that of instantly claimed. Therefore, the property of the methylnaltrexone composition to extend the lifespan in the chronic non-cancerous pain patient must necessarily be present because products of identical chemical composition cannot exert mutually exclusive properties when prepared or used in the same manner under the same circumstances. In other words, if the prior art teaches the identical chemical or physical structure of the composition, (i.e., the same active agents, methylnaltrexone and morphine), and the composition is used in the same manner (i.e., administered in the same manner to the same chronic non-cancerous pain patient), the properties that Applicant discloses and/or claims must necessarily be present. Furthermore, as stated in MPEP 2112.02, “[u]nder the principles of inherency, if a prior art device, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered anticipated by the prior art device.”
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 1-2, 13, 19, 27, 32-34, 36, 41, 47 and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan (US2015/0190523 published 07/09/2015).
Yuan teaches the method of treating chronic pain in a subject in need comprising administering to said subject a therapeutically effective amount of a composition comprising methylnaltrexone formulated with the phospholipid phosphatidylcholine (PC) (claim 23, 32). Regarding claims 2 and 13, treatment of chronic non-malignant pain is embodied within the teachings of Yuan, wherein non-malignant pain is identified as non-cancerous pain, such as back pain, fibromyalgia, migraines, neuropathic pain or osteoarthritis ([0105]).
Regarding claim 19 and 47, oral administration of said therapeutically effective amount of a composition comprising methylnaltrexone formulated with the phospholipid phosphatidylcholine (PC) is taught by Yuan, wherein said composition is formulated as an oral solution ([0089], [0099]-[0100]. Yuan teaches administration of said oral methylnaltrexone composition in a dose of 0.1 mg/kg body weigh to about 20 mg/kg body weight, which lies inside the presently claimed range. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Regarding claim 27, 34, and 41 Yuan teaches that patients receiving said therapeutically effective amount of a composition comprising methylnaltrexone formulated with the phospholipid phosphatidylcholine (PC) are subjects who are receiving oral or intravenous opioid therapy, including the opioid hydrocodone ([0104]-[0105], [0107]-[0110]). Regarding the scope of claim 32, administration of methylnaltrexone formulated as the bromide salt is taught by Yuan ([0057]-[0058]).
Regarding the limitation of claim 56, as the methodology embraced within claims 23 and 32 of Yuan is silent as to the chronic pain patient experiencing opioid induced constipation, the examiner has interpreted that said chronic pain patient population administered a therapeutically effective amount of a composition comprising methylnaltrexone formulated with the phospholipid phosphatidylcholine (PC) does not comprise opioid induced constipation, which reads on the claimed limitations.
Therefore, one of ordinary skill in the art prior to the time of the invention would have found it prima facie obvious to treat a subject comprising chronic non-malignant pain comprising administering a therapeutically effective amount of methylnaltrexone to the afflicted patient in view of Yuan.
Applicant is reminded of MPEP 2144.07 wherein the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Applicant is also reminded that “[I]t is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985).” In the instant case, the treatment of chronic non-malignant pain was one of 12 species of pain disclosed by Yuan to be treated with the administration of methylnaltrexone ([0104]-[0105], claims 23, 32). Accordingly, said artisan would have readily predicted that administration of said therapeutically effective amount of a composition comprising methylnaltrexone formulated with the phospholipid phosphatidylcholine (PC) would have effectively treated the chronic non-malignant pain in the afflicted subject.
Regarding the capacity of the administered 0.1 to 20 mg/kg of methylnaltrexone to reduce mortality risk in the administered subject with chronic non-malignant pain as taught by Yuan above and extend the lifespan for at least 30 days (claim 33), properties that accrue from the process step of administering the same therapeutically effective amount of methylnaltrexone to the same patient population are considered characteristic features of the claimed therapeutic regimen.
It is noted that MPEP 2112 discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph).
In the present case the burden is shifted to Applicant to prove that the administered regimen of 0.1 to 20 mg/kg of methylnaltrexone to the patient with chronic non-malignant pain embodied within the teachings of Yuan above does not reduce mortality risk in the administered patient, nor does not extend the lifespan for at least 30 days.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Yuan (US2015/0190523 published 07/09/2015) as applied to claims 1-2, 13, 19, 27, 32-34, 36, 41, 47 and 56 above in view of Webster (Journal of Pain Research Vol. 11 pages 1503-1510. Published 2018).
Yuan teaches the method of treating chronic pain in a subject in need comprising administering to said subject a therapeutically effective amount of a composition comprising methylnaltrexone formulated with the phospholipid phosphatidylcholine (PC) (claim 23, 32). Regarding claims 2 and 13, treatment of chronic non-malignant pain is embodied within the teachings of Yuan, wherein non-malignant pain is identified as non-cancerous pain, such as back pain, fibromyalgia, migraines, neuropathic pain or osteoarthritis ([0105]). Oral administration of said therapeutically effective amount of a composition comprising methylnaltrexone formulated with the phospholipid phosphatidylcholine (PC) is taught by Yuan, wherein said composition is formulated as an oral solution ([0089], [0099]-[0100]. Yuan teaches administration of said oral methylnaltrexone composition in a dose of 0.1 mg/kg body weight to about 20 mg/kg body weight, which lies inside the presently claimed range. Applicant is reminded of MPEP 2144.05 wherein the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
The difference between the methodology of Yuan and that of the present claim is that Yuan does not specifically teach wherein the patients comprising chronic non-cancerous pain treated with naltrexone are less than 60 years old.
Webster teaches the method of treating a patient comprising chronic non-cancerous pain in a subject being treated with > 50 mg oral morphine equivalent dose comprising administering a therapeutically effective amount of methylnaltrexone (abstract, page 1504 right col. through page 1505 left col.).
Regarding claim 9, patients >18 years with a median age of 51 years were treated with the disclosed methylnaltrexone therapeutic regimen (page 1504 right col. Table 1). Oral administration of methylnaltrexone in 150 mg tablet form in a dose of one, two or three tablets per day is taught by Webster (page 1505 left-right col.). Mean pain intensity scores remained stable with the combination of methylnaltrexone and morphine regimen to the chronic non-cancer pain patient (Table 2). Webster teaches that said regimen results in significant dos-related improvement of opioid induced constipation without compromising analgesia by the opioid therapeutic (page 1508, right col).
Therefore, one of ordinary skill in the art of treating a subject with chronic non-malignant pain comprising administering a therapeutically effective amount of methylnaltrexone to the afflicted patient in view of Yuan, said skilled artisan would have found it prima facie obvious to administer said methylnaltrexone therapeutic regimen to patients under the age of 60 in view of Webster.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, it was known in the art of Webster that methylnaltrexone is efficacious at treating chronic non-cancerous pain in patients under 60 years old. Accordingly, said skilled artisan would have readily predicted that administration of a therapeutically effective amount of methylnaltrexone to a chronic non-malignant pain patient who is under the age of 60 would have effectively treated said pain in the afflicted subject.
Claim 58 is rejected under 35 U.S.C. 103 as being unpatentable over Yuan (US2015/0190523 published 07/09/2015) as applied to claims 1-2, 13, 19, 27, 32-34, 36, 41, 47 and 56 above in view of Wagoner (WO2006/127898 published 11/30/2006).
As disclosed above, Yuan (US2015/0190523 published 07/09/2015) teaches the method of treating chronic pain in a subject in need comprising administering to said subject a therapeutically effective amount of a composition comprising methylnaltrexone formulated with the phospholipid phosphatidylcholine (PC) (claim 23, 32). Regarding claims 2 and 13, treatment of chronic non-malignant pain is embodied within the teachings of Yuan, wherein non-malignant pain is identified as non-cancerous pain, such as back pain, fibromyalgia, migraines, neuropathic pain or osteoarthritis ([0105]).
However, Yuan does not specifically teach determining whether the subject has or has previously had an increased risk of death based on the presence of various risk factors optionally as listed under table 3. As shown in table 3, diabetes is identified as one of the disclosed risk factors.
Wagoner (WO2006/127898 published 11/30/2006) teaches that methylnaltrexone is art-recognized as efficacious at treating diabetes in a subject in need (page 30 line 30 to page 31 line 10).
Therefore, one of ordinary skill in the art of treating a subject with chronic non-malignant pain comprising administering a therapeutically effective amount of methylnaltrexone to the afflicted patient in view of Yuan, said skilled artisan would have found it prima facie obvious to determine whether said chronic non-malignant pain patient has an increased risk of death, including comprising the risk factor diabetes in view of the teachings of Wagoner.
MPEP 2143 provides rationale for a conclusion of obviousness including (A): Combining prior art elements according to known methods to obtain predictable results;
In the present case, it was known in the art of Wagoner that methylnaltrexone is efficacious for the treatment of diabetes. Accordingly, said skilled artisan would have readily predicted that administration of a therapeutically effective amount of methylnaltrexone to the afflicted chronic non-malignant pain patient further comprising diabetes would have effectively treated both said pain and metabolic disorder in the afflicted subject.
Conclusion
In view of the rejections set forth above, no claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGE W KOSTURKO whose telephone number is (571)270-5903. The examiner can normally be reached M-F 9:00-5:30.
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/GEORGE W KOSTURKO/Examiner, Art Unit 1621