DETAILED ACTION
All rejections and objections not mentioned below have been withdrawn.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/16/2026 has been entered.
Claim Interpretation
The examiner has not written a 112a rejection based on lack of enablement because the prior art used to reject under 103 would suggest enablement. However, if the applicant argues that the prior art supplied by the examiner does not provide support for the claims and the applicant has also not filed any IDS references or experimental evidence supporting the enablement of the claims then the claims must be assumed to be not enabled as no evidence besides the prior art in the 103 rejections provides for the claims being enabled.
Response to Arguments
Applicant's arguments filed 01/08/2026 have been fully considered but they are not persuasive.
Rejections under 35 USC 103
The applicant argues that the rejection had no art that included thyroid hormones this has been updated in the new rejection below based on applicants claim amendment.
The applicant further argue that the obviousness rejection fails to provide the required motivation to combine the teachings of the references as well as a reasonable expectation of success. This argument is not persuasive because the examiner provides the motivation as "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). One would have a reasonable expectation of success because all components were known to be used for the same purpose separately.
The applicant argues “Support for Applicant's position is that Fifield is used to show that rapamycin is known to block a specific predator-induced hyperaousal in mice. No support that links the specific predator-induced hyperarousal in mice with PTSD in humans is provided and no reasonable expectation of success can be ascertained by this association in mice”. This is not considered persuasive because animal models are often used for drug studies in placement of human models for safety/ ethical reasons to see how drug may effect a living human without harming a person. This would be obvious to one of ordinary skill in the art. Fifield states that the experiment is an animal model “In the current study, we examined the effects of systemic rapamycin on predator stress-induced non-associative fear memories. Predator stress is an ecologically relevant animal model of PTSD in that it presents animals with a traumatic event (exposure to a predator or predator cues) that they may encounter in nature”(page 458) this in combination with the discussion of human PTSD (page 457) makes it clear that the mice are an animal model used to provide insight into how drugs may behave in humans.
The applicant also argues “No motivation to provide icosapent ethyl to patients outside of this defined omega-3 deficiency population is provided and therefore, it cannot be said that a reasonable expectation of success exists for the claimed methods”. This argument is not found persuasive because Chilton teaches VASCEPA for PTSD treatment and the FDA provides evidence that VASCEPA contains icosapent ethyl.
Double patenting
The applicant argued that: “Applicants assert that the claimed combination does not contain all of the limitations of the present claims including at least the dosing regimen of the first and second pharmaceutical composition at least once a month but no more than 3 times per week. Accordingly, Applicants assert that this rejection has been overcome”. This argument is not persuasive because while the exact dosing schedule is not provided optimizing a dosing schedule is routine experimentation and would be obvious to one of ordinary skill in the art. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.)
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/166,752, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. A claim by claim analysis indicated a lack of support for thyroid hormone (all claims) in the application No. 63/166,752 and thus a date of 03/28/2022 was used for priority.
Information Disclosure Statement
No IDS has been filed.
Claim Rejections - 35 USC § 103 Updated Due to Amendments
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 10, 11, 14, 18 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over:
FIFIELD (Fifield et al., “Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal”, Behavioral Brain Research, August 31, 2013, previously provided to Applicants),
In view of:
Chilton (Chilton et al., WO2015054645A1, 04/16/2015, previously provided to Applicants)
Agid (Agid et al., Triiodothyronine Augmentation of Selective Serotonin Reuptake Inhibitors in Posttraumatic Stress Disorder, J Clin Psychiatry 2001: 62· 169-173.)
As evidenced by
FAVERIO (Faverio et al., ”Long-term macrolides in diffuse interstitial lung diseases”, Eur Res Review, 2017, previously provided to Applicants) .
FDA (FDA, VASCEPA®, 12/2019, previously provided to Applicants)
Perrotta (Perrotta et al., The Thyroid Hormone Triiodothyronine Controls Macrophage Maturation and Functions: Protective Role during Inflammation, The American Journal of Pathology Volume 184, Issue 1, January 2014, Pages 230-247)
Claims 10, 11, 14, 18 and 21-23 are drawn to methods of treating, preventing, reducing the incidence of or severity of PTSD by administering a composition of two or more mTOR inhibitors (one of which is icosapent ethyl) and an effective amount of thyroid hormone. Claim 14 is drawn to the second mTOR inhibitor is rapamycin (a non-antibiotic macrolide). Claim 21-22 is drawn to wherein the thyroid hormone is administered concurrently. Claim 23 wherein the thyroid hormone is an amount to promote euthyroiduism.
Determining the scope and contents of the prior art
FIFIELD teaches administering rapamycin, an mTOR inhibitor, to rats (abstract). FIFIELD teaches that rapamycin blocks predator stress-induced hyperarousal (results 3.2 and figure 3). FIFIELD teaches that the predator stress is an animal model of PTSD (page 458 right col). This helps teach claims 10 and 11.
FAVERIO is relied upon for the beneficial teaching that rapamycin is a non-antibiotic macrolide (page 2 second paragraph). This helps teach rapamycin is a compound of claim 14. This teaches instant claim 18.
FIFIELD teaches that rapamycin was injected (2.2). The Examiner understands and interprets the rapamycin injection as rapamycin was formulated as a pharmaceutical composition (thus being able to be injected).
FIFIELD teaches that rapamycin’s effect on predator stress-induced hyperarousal is long-lasting (3.3 page 460).
FIFIELD teaches that mTOR regulation of protein translation is required for the formation of both associative and non-associative fear memories and that mTOR activation may contribute to the development of acquired anxiety disorders such as PTSD (abstract). This helps teach claims 10 and 11.
Chilton teaches “Levels of omega-6 (n-6) and omega-3 (n-3), long chain polyunsaturated fatty acids (LcPUFAs) such as arachidonic acid (AA; 20:4, n-6), eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3) impact a wide range of biological activities including immune signaling, inflammation, brain development and function as well as human diseases ranging from cardiovascular disease (including heart disease and stroke), diabetes, cancers, Alzheimer's disease and mental disorders.”(page 1) and “Currently there are no verified available biomarkers for post-traumatic stress disorders (PTSD) to identify who is at risk or who might benefit from a specific therapy. Numerous studies suggest that synatoneogenesis and neuronal plasticity are important for repair of brain tissue injury, including psychological traumas. Levels of n-3 LcPUFAs have been demonstrated to be involved in these processes. A case-control of active-duty suicides indicated lower serum levels of the n-3 LcPUFA, DHA were associated with a marked increase in suicide risk” (page 4). Additionally, Chilton teaches “In some embodiments, the dietary supplement can be, but is not limited to, long chain omega-3-enriched triglycerides, phospholipids, Krill oil, esters, ethyl esters and any combination thereof” (page 11) and suggests administering icosapent ethyl ( Vascepa) (page 11, reference claim 12), “The method of claim 9, wherein the medical food and/or prescription product is a triglyceride, phospholipid or ester version of a omega-3 polyunsaturated fatty acid that contains a higher dose /or concentration of omega-3 polyunsaturated fatty acid than dietary supplements, such as Epanova, Lovaza, Vascepa, or any combination thereof” for PTSD (reference claim 15) “The method of any of claims 1-12, wherein the subject is an adult that has, or is suspected of having depression, bipolar disorder, schizophrenia, panic disorder, obsessive compulsive disorder (OCD), dementia, Alzheimer's disease, post traumatic stress disorder (PTSD) or any combination thereof, as a result of, or associated with 03D”. This helps teach claims 10 and 11.
The FDA gives evidence that “Each VASCEPA capsule contains either 0.5 grams of icosapent ethyl (in a 0.5 gram capsule) or 1 gram of icosapent ethyl (in a 1 gram capsule)” (section 11). This helps to teach claims 10 and 11.
Agid teaches “The positive effects of T 3 in these patients with PTSD could have the same basis as the effect of the hormone in depression”( page 172) and “Triiodothyronine Augmentation of Selective Serotonin Reuptake Inhibitors in Posttraumatic Stress Disorder” (title). Agid also teaches “Their findings suggest that T 3 may act by augmenting synaptic availability of serotonin over and above the effect of a concurrently administered antidepressant”(page 172) and “However, most depressed patients are euthyroid, and no consistent relationship exists between basal thyroid hormone levels and responses to T3”(page 172). This helps to teach claims 10 and 11 and 23. It would be obvious to one of ordinary skill in the art to try and promote euthyroiduism because irregular levels could cause undesired side effects.
Perrotta provides evidence that Triiodothyronine is a Thyroid Hormone (title).
Ascertaining the differences between the prior art and the claims at issue
While FIFIELD teaches administering rapamycin, an mTOR inhibitor, to rats (as an animal model of PTSD) (abstract and page 458), and teaches that rapamycin blocks predator stress-induced hyperarousal (results 3.2 and figure 3), FIFIELD does not teach icosapent ethyl (IPE).
While Chilton teaches icosapent ethyl (IPE) for PTSD, Chilton does not teach it in combination with another mTOR inhibitor (claims 10 and 11).
The FDA teaches VASCEPA capsule contains icosapent ethyl but does not teach the instant methods.
Agid teaches Triiodothyronine for PTSD but not mTOR inhibitors or icosapent ethyl (IPE) for PTSD.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development, and chemical synthesis, of mTOR inhibitors and therapeutics useful for treating PTSD, and possesses the technical knowledge necessary to make adjustments to the therapeutics to optimize/enhance the pharmacokinetic properties of mTOR inhibitors and their effectiveness. Said artisan has also reviewed the problems in the art as regards to bioavailability of these therapeutics and understands the solutions that are widely-known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
The instant claims 10, 11, 14, 18, 21-22 are prima facie obvious in light of the combination of references FIFIELD (as evidenced by FAVERIO), and Chilton (as evidenced by the FDA) and Agid (as evidenced by Perrotta).
The artisan would find it obvious to use rapamycin (a mTOR inhibitor) to treat PTSD. FIFIELD teaches administering rapamycin to rats, which were used as an animal model of PTSD (abstract and page 458). The artisan would expect that rapamycin would treat PTSD since rapamycin is known to block predator stress-induced hyperarousal (FIFIELD results 3.2 and figure 3) in mice. This helps teach claims 10, 11, 14, and 18.
FAVERIO is relied upon for the beneficial teaching that rapamycin is a non-antibiotic macrolide (page 2 second paragraph). This helps teach rapamycin is a compound of claim 14. Applicants also admit to such with their claim construction further defining “rapamycin” as a “non-antibiotic macrolide mTOR inhibitor”.
The artisan would be motivated to add icosapent ethyl (ester version of a omega-3 polyunsaturated fatty acid) and Triiodothyronine and Selective Serotonin Reuptake Inhibitors. FIFIELD teaches that mTOR activation contributes to the development of PTSD (abstract). It is prima facie obvious to combine one PTSD-treating compound (icosapent ethyl, Triiodothyronine and Selective Serotonin Reuptake Inhibitors) with another PTSD-treating composition (mTOR inhibitor results 3.2 and figure 3 FIFIELD) in order to form a composition to be used for the very same purpose (treating PTSD). "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted)
The artisan would be motivated and expected to administer the mTOR inhibitors (“icosapent ethyl” and rapamycin, Triiodothyronine and Selective Serotonin Reuptake Inhibitors) as a “pharmaceutical composition” since both have known medicinal qualities (above). The artisan would have been motivated to administer this pharmaceutical composition to a subject with PTSD. The artisan would have expected the pharmaceutical composition to treat PTSD because the pharmaceutical composition is effective in the PTSD animal model (FIFIELD page 458 right col) and because icosapent ethyl, an ester version of a omega-3 polyunsaturated fatty acid, has been suggested for treatment of PTSD patients who have been found to be deficient in omega-3 polyunsaturated fatty acids because “Numerous studies suggest that synatoneogenesis and neuronal plasticity are important for repair of brain tissue injury, including psychological traumas. Levels of n-3 LcPUFAs have been demonstrated to be involved in these processes” (page 4) and because Triiodothyronine and Selective Serotonin Reuptake Inhibitors have shown improvement in PTSD depression. This teaches claims 10, 11, 14, and 18.
While the exact dosing schedule is not provided optimizing a dosing schedule is routine experimentation and would be obvious to one of ordinary skill in the art. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.)
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious before the effective filing date of the claimed invention to one of ordinary skill in the art, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 10, 11, 14, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over:
FIFIELD (Fifield et al., “Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal”, Behavioral Brain Research, August 31, 2013, previously provided to Applicants),
As evidenced by
FAVERIO (Faverio et al., ”Long-term macrolides in diffuse interstitial lung diseases”, Eur Res Review, 2017, previously provided to Applicants) .
In view of
• Chilton (Chilton et al., WO2015054645A1, 04/16/2015)
QUERVAIN (Quervain, “Glucocorticoid-induced reduction of traumatic memories: implications for the treatment of PTSD”, Progress in Brain Research, Vol. 167, 2007, previously provided to Applicants),
Agid (Agid et al., Triiodothyronine Augmentation of Selective Serotonin Reuptake Inhibitors in Posttraumatic Stress Disorder, J Clin Psychiatry 2001: 62· 169-173.)
As evidenced by
CLEVELAND CLINIC (“Corticosteroids”, Cleveland Clinic, January 20, 2020, previously provided to Applicants),
FDA (FDA, VASCEPA®, 12/2019)
Perrotta (Perrotta et al., The Thyroid Hormone Triiodothyronine Controls Macrophage Maturation and Functions: Protective Role during Inflammation, The American Journal of Pathology Volume 184, Issue 1, January 2014, Pages 230-247)
The references FIFIELD, FAVERIO, Chilton, Agid, Perrotta and the FDA has been discussed supra and do not disclose corticosteroid (claim 19).
Claim 19 is drawn to the pharmaceutical composition further comprises corticosteroid.
Determining the scope and contents of the prior art
QUERVAIN teaches administering a low-dose cortisol to patient with PTSD (Conclusions). QUERVAIN teaches that cortisol reduced symptoms of traumatic memories and teaches a prolonged effect of the cortisol treatment (abstract). This helps teach claim 19.
CLEVELAND CLINIC is relied upon for the beneficial teaching that corticosteroids are the synthetic version of cortisol, which is naturally produced by the human body (page 1). The Examiner understands that cortisol and corticosteroid are functionally the same.
Ascertaining the differences between the prior art and the claims at issue
The references FIFIELD, FAVERIO, Chilton, Agid, Perrotta and the FDA has been discussed supra and do not disclose corticosteroid (claim 19). While QUERVAIN teaches administering cortisol to patients with PTSD (Conclusions), QUERVAIN does not teach the instant method of administering an mTOR inhibitor.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development, and chemical synthesis, of mTOR inhibitors and therapeutics useful for treating PTSD, and possesses the technical knowledge necessary to make adjustments to the therapeutics to optimize/enhance the pharmacokinetic properties of mTOR inhibitors and their effectiveness. Said artisan has also reviewed the problems in the art as regards to bioavailability of these therapeutics and understands the solutions that are widely-known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
The instant claims 10, 11, 14, and 19, are prima facie obvious in light of the combination of references FIFIELD (as evidenced by FAVERIO), and Chilton (as evidenced by the FDA) and Agid (as evidenced by Perrotta) and QUERVAIN (as evidenced by CLEVELAND CLINIC).
The artisan would have been motivated to add additional agent of corticosteroid. QUERVAIN teaches administering a low-dose cortisol to patient with PTSD, and teaches that cortisol reduced symptoms of traumatic memories (Conclusion and abstract). The artisan would expect that adding a corticosteroid, a known treatment for PTSD (QUERVAIN Conclusion and abstract; as evidenced by CLEVELAND CLINIC page 1) to the pharmaceutical composition containing an mTOR inhibitor would also result in a functional PTSD composition/treatment. It is prima facie obvious to combine one PTSD-treating compound (corticosteroid; Abstract and Conclusion QUERVAIN) with another PTSD-treating composition (mTOR inhibitor results 3.2 and figure 3 FIFIELD, or icosapent ethyl (Chilton or , Triiodothyronine and Selective Serotonin Reuptake Inhibitors ) in order to form a composition to be used for the very same purpose (treating PTSD). This teaches claim 19.
While the exact dosing schedule is not provided optimizing a dosing schedule is routine experimentation and would be obvious to one of ordinary skill in the art. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.)
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious before the effective filing date of the claimed invention to one of ordinary skill in the art, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 10, 11, 14, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over:
FIFIELD (Fifield et al., “Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal”, Behavioral Brain Research, August 31, 2013, previously provided to Applicants),
As evidenced by
FAVERIO (Faverio et al., ”Long-term macrolides in diffuse interstitial lung diseases”, Eur Res Review, 2017, previously provided to Applicants) .
And in view of
AHMED (Ahmed et al., “Vitamin E prevents the cognitive impairments in post-traumatic stress disorder rat model: behavioral and molecular study”, Psychopharmacology, November 16, 2019, previously provided to Applicants).
• Chilton (Chilton et al., WO2015054645A1, 04/16/2015)
Agid (Agid et al., Triiodothyronine Augmentation of Selective Serotonin Reuptake Inhibitors in Posttraumatic Stress Disorder, J Clin Psychiatry 2001: 62· 169-173.)
As evidenced by
FDA (FDA, VASCEPA®, 12/2019)
Perrotta (Perrotta et al., The Thyroid Hormone Triiodothyronine Controls Macrophage Maturation and Functions: Protective Role during Inflammation, The American Journal of Pathology Volume 184, Issue 1, January 2014, Pages 230-247)
The references FIFIELD, FAVERIO, Chilton, Agid, Perrota and the FDA has been discussed supra and do not disclose the specific additional active ingredients listed in claim 20.
Claim 20 is drawn to the composition further comprises an additional agent.
Determining the scope and contents of the prior art
AHMED teaches vitamin E prevented PTSD-caused impairment of memory (results). AHMED used a rat model of PTSD-like behavior (methods). This helps teach claim 20.
Ascertaining the differences between the prior art and the claims at issue
The references FIFIELD, FAVERIO, Chilton, Agid, Perrota and the FDA has been discussed supra and do not disclose the specific additional active ingredients listed in claim 20. While AHMED teaches vitamin E prevented PTSD-caused impairment of memory in a rat model of PTSD (results and methods), AHMED does not teach the instant method of administering an mTOR inhibitor.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development, and chemical synthesis, of mTOR inhibitors and therapeutics useful for treating PTSD, and possesses the technical knowledge necessary to make adjustments to the therapeutics to optimize/enhance the pharmacokinetic properties of mTOR inhibitors and their effectiveness. Said artisan has also reviewed the problems in the art as regards to bioavailability of these therapeutics and understands the solutions that are widely-known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
The instant claims 10, 11, 14, and 20 are prima facie obvious in light of the combination of references FIFIELD (as evidenced by FAVERIO), Chilton (as evidenced by the FDA), and Agid (as evidenced by Perrotta) and in view of AHMED.
The artisan would have been motivated to add additional agent of vitamin E. AHMED teaches vitamin E prevented PTSD-caused impairment of memory in a rat model of PTSD (results, methods). The artisan would expect that adding a vitamin E, a known treatment for PTSD (AHMED results and methods) to the pharmaceutical composition containing an mTOR inhibitor would also result in a functional PTSD composition/treatment. It is prima facie obvious to combine one PTSD-treating compound (vitamin E results and methods AHMED) with another PTSD-treating composition (mTOR inhibitor FIFIELD results 3.2 and figure 3, or icosapent ethyl (Chilton ), Triiodothyronine and Selective Serotonin Reuptake Inhibitors ) in order to form a composition to be used for the very same purpose (treating PTSD). This teaches claim 20.
While the exact dosing schedule is not provided optimizing a dosing schedule is routine experimentation and would be obvious to one of ordinary skill in the art. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.)
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious before the effective filing date of the claimed invention to one of ordinary skill in the art, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 10, 14 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over :
FIFIELD (Fifield et al., “Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal”, Behavioral Brain Research, August 31, 2013, previously provided to Applicants),
In view of
Agid (Agid et al., Triiodothyronine Augmentation of Selective Serotonin Reuptake Inhibitors in Posttraumatic Stress Disorder, J Clin Psychiatry 2001: 62· 169-173.)
As evidenced by
FAVERIO (Faverio et al., ”Long-term macrolides in diffuse interstitial lung diseases”, Eur Res Review, 2017, previously provided to Applicants) .
Perrotta (Perrotta et al., The Thyroid Hormone Triiodothyronine Controls Macrophage Maturation and Functions: Protective Role during Inflammation, The American Journal of Pathology Volume 184, Issue 1, January 2014, Pages 230-247)
In view of
Jones (Jones et al., US-20170157212-A1, 2017)
• Chilton (Chilton et al., WO2015054645A1, 04/16/2015)
As evidenced by
FDA (FDA, VASCEPA®, 12/2019)
All references but Jones have been discussed supra and do not disclose metformin (claim 16).
Jones teaches “Illustrative indirect mTOR inhibitors include metformin…”[0181]. This helps to teach claim 16.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified FIFIELD, FAVERIO, Chilton, Agid, Perrotta and FDA which teaches it is prima facie obvious to combine one PTSD-treating compound (icosapent ethyl) with another PTSD-treating composition (mTOR inhibitor results 3.2 and figure 3 FIFIELD, Triiodothyronine and Selective Serotonin Reuptake Inhibitors) in order to form a composition to be used for the very same purpose (treating PTSD) with Jones. It would be obvious to add another mTOR inhibitor (metformin) to treat PTSD, given that mTOR activation contributes to the development of PTSD. Furthermore, it is prima facie obvious to combine two PTSD treating compounds (rapamycin; FIFIELD abstract and page 458, and metformin, Jones ) with another PTSD treating compound(icosapent ethyl, Triiodothyronine and Selective Serotonin Reuptake Inhibitors) in order to form a composition to be used for the very same purpose (treating PTSD). "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
While the exact dosing schedule is not provided optimizing a dosing schedule is routine experimentation and would be obvious to one of ordinary skill in the art. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.)
Claim(s) 10, 14 and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over :
FIFIELD (Fifield et al., “Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal”, Behavioral Brain Research, August 31, 2013, previously provided to Applicants),
As evidenced by
FAVERIO (Faverio et al., ”Long-term macrolides in diffuse interstitial lung diseases”, Eur Res Review, 2017, previously provided to Applicants) .
In view of
KELLOGG ( KELLOGG, Dean, US20180015074A1, 2018)
• Chilton (Chilton et al., WO2015054645A1, 04/16/2015)
In view of
Agid (Agid et al., Triiodothyronine Augmentation of Selective Serotonin Reuptake Inhibitors in Posttraumatic Stress Disorder, J Clin Psychiatry 2001: 62· 169-173.)
As evidenced by
FDA (FDA, VASCEPA®, 12/2019)
Perrotta (Perrotta et al., The Thyroid Hormone Triiodothyronine Controls Macrophage Maturation and Functions: Protective Role during Inflammation, The American Journal of Pathology Volume 184, Issue 1, January 2014, Pages 230-247)
All references but KELLOGG have been discussed supra and do not disclose fisetin and fisetin derivatives (claim 17).
KELLOGG teaches “In specific embodiments, the inhibitor of an mTOR pathway is rapamycin and/or a rapamycin analog. Examples of rapamycin analogs include temsirolimus, everolimus, deforolimus, CCI-779, curcumin, Green tea extract standardized to 70% EGCG, transresveratrol, fisetin, salicin extracted from white willow, or a combination thereof”[0023]. This helps to teach claim 17.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified FIFIELD, FAVERIO, Chilton, Agid, Perrotta and FDA which teaches it is prima facie obvious to combine one PTSD-treating compound (icosapent ethyl) with another PTSD-treating composition (mTOR inhibitor results 3.2 and figure 3 FIFIELD, Triiodothyronine and Selective Serotonin Reuptake Inhibitors) in order to form a composition to be used for the very same purpose (treating PTSD) with KELLOGG. It would be obvious to add another mTOR inhibitor (fisetin) to treat PTSD, given that mTOR activation contributes to the development of PTSD. Furthermore, it is prima facie obvious to combine two mTOR inhibitors (rapamycin; FIFIELD abstract and page 458, and fisetin, KELLOGG ) with another PTSD treating compound ( icosapent ethyl and Triiodothyronine and Selective Serotonin Reuptake Inhibitors) in order to form a composition to be used for the very same purpose (treating PTSD). "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
While the exact dosing schedule is not provided optimizing a dosing schedule is routine experimentation and would be obvious to one of ordinary skill in the art. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.)
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 10-11, 14, 16, 17, 18, 19 and 20-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 of U.S. Patent No. US 12220405 B2 in view of:
• FIFIELD (Fifield et al., “Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal”, Behavioral Brain Research, August 31, 2013, previously provided to Applicants)
U.S. Patent No. US 12220405 B2 claims:
“1. A method of treating, reducing the incidence of, or reducing the severity of hepatic steatosis comprising administering an effective amount of a pharmaceutical composition of one or more mTOR inhibitors selected from the group consisting of an omega-3 fatty acid derivative, a biguanide antihyperglycemic agent, a flavonoid selected from the group consisting of fisetin and fisetin derivatives, a macrolide, and any combination thereof; and an effective amount of one or more thyroid hormones, wherein the one or more thyroid hormones include liothyronine.
2. The method of claim 1, wherein the omega-3 fatty acid derivative is icosapent ethyl.
3. The method of claim 1, wherein the biguanide antihyperglycemic agent is metformin.
4. The method of claim 1, wherein the flavonoid is selected from the group consisting of fisetin and a fisetin derivative.
5. The method of claim 1, wherein the macrolide is rapamycin.
6. The method of claim 1, wherein the pharmaceutical composition further comprises an effective amount of one or more other active agents selected from the group consisting of vitamin B derivatives, quercetin, resveratrol and NAD+.” Thus U.S. Patent No. US 12220405 B2 claims a chemical composition that is made up of mTOR inhibitors. This helps to teach claims 10-11, 14, 16, 17, 18, and 19 and 20.
U.S. Patent No. US 12220405 B2 does not claim the method of treating acquired brain injuries, PTSD, or a degenerative neurological disorder (all claims).
FIFIELD has been discussed supra.
It would have been prima facie obvious to one of ordinary skill in the art to have modified U.S. Patent No. US 12220405 B2 with FIFIELD because U.S. Patent No. US 12220405 B2 teaches a combination of mTOR inhibitors and FIFIELD teaches mTOR inhibitors can be used to treat PTSD. FIFIELD teaches that mTOR activation contributes to the development of PTSD (abstract). It would be obvious to add another mTOR inhibitor to treat PTSD, given that mTOR activation contributes to the development of PTSD. Furthermore, it is prima facie obvious to combine one mTOR inhibitor (rapamycin; FIFIELD abstract and page 458) with another mTOR inhibitor (icosapent ethyl) in order to form a composition to be used for the very same purpose (treating PTSD). The artisan would be motivated and expected to administer the mTOR inhibitors (icosapent ethyl and rapamycin) as a “pharmaceutical composition” since both have known medicinal qualities (above). The artisan would have been motivated to administer this pharmaceutical composition to a subject with PTSD. The artisan would have expected the pharmaceutical composition to treat PTSD because the pharmaceutical composition is effective in the PTSD animal model (FIFIELD page 458 right col). Additionally it would have been obvious to add vitamin B derivatives to the composition because it had been used before in combination with a composition that treated a mTOR related disease and so one would be motivated to do so since the composition would treat PTSD along a similar pathway. It would be obvious to one of ordinary skill in the art to try and promote euthyroiduism because irregular levels could cause undesired side effects.
While the exact dosing schedule is not provided optimizing a dosing schedule is routine experimentation and would be obvious to one of ordinary skill in the art. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.)
Claims 10, 11, 14, 16, 17, 18 and 19, 21-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 11, 12, 14-17, 19 and 20 of copending Application No. 17/356,319 in view of:
• FIFIELD (Fifield et al., “Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal”, Behavioral Brain Research, August 31, 2013, previously provided to Applicants)
Application No. 17/356,319 claims:
“11. (Currently Amended) A method of, or treating, preventing, or reducing theincidence and/or severity of the secondary effects of primary cancer treatments, in a subject receiving a primary cancer treatment comprising administering an effective amount of a pharmaceutical composition comprising three or more mTOR inhibitors to said subject in need thereof.
12. (Previously Presented) The method of claim 11, wherein the three or more mTOR inhibitors are selected from the group consisting of: icosapent ethyl, a biguanide antihyperglycemic agent, a flavonoid, a macrolide and combinations thereof.
13. (Canceled)
14. (Original) The method of claim 12, wherein the biguanide antihyperglycemic agent is metformin.
15. (Previously Presented) The method of claim 12, wherein the flavonoid is fisetin.
16. (Original) The method of claim 12, wherein the macrolide is rapamycin.
17. (Original) The method of claim 12, wherein the pharmaceutical composition further comprises an effective amount of one or more thyroid hormones.
18. (Original) The method of claim 17, wherein the one or more thyroid hormones comprises liothyronine.
19. (Previously Presented) The method of claim 18, wherein when at least one of the three or more mTOR inhibitors is a flavonoid it is fisetin.
20. (Previously Presented) The method of claim 17, wherein each of the three or more mTOR inhibitors are selected from the group consisting of icosapent ethyl, metformin, fisetin, rapamycin, and any combination thereof, and wherein the one or more thyroid hormones comprises liothyronine.
21. (Previously Presented) The method of claim 17, wherein at least one of the three or more mTOR inhibitors is a macrolide and wherein the macrolide is administered prior to the administration of any other of the three or more mTOR inhibitors and the one or more thyroid hormones. Response to Non-Final Office Action Issued May 31, 2024 22. (Currently Amended) A pharmaceutical composition for adjuvant and complementary therapy to treat, prevent, reduce the incidence of, or reduce the severity of cancer or one or more secondary effects of primary cancer treatments comprising: an effective amount of fisetin; an effective amount of icosapent ethyl; an effective amount of an mTOR inhibitor selected from the group consisting of a biguanide antihyperglycemic agent, a macrolide, and any combination thereof; and at least one additional mTOR inhibitor(s.” This helps to teach claims 10, 11, 14, 16, 17, 18 and 19.
FIFIELD has been discussed supra.
It would have been prima facie obvious to one of ordinary skill in the art to have modified U.S. Application No. 17/356,319with FIFIELD because U.S. Application No. 17/356,319 teaches a combination of mTOR inhibitors and FIFIELD teaches mTOR inhibitors can be used to treat PTSD. FIFIELD teaches that mTOR activation contributes to the development of PTSD (abstract). It would be obvious to add another mTOR inhibitor to treat PTSD, given that mTOR activation contributes to the development of PTSD. Furthermore, it is prima facie obvious to combine one mTOR inhibitor (rapamycin; FIFIELD abstract and page 458) with another mTOR inhibitor (icosapent ethyl) in order to form a composition to be used for the very same purpose (treating PTSD). The artisan would be motivated and expected to administer the mTOR inhibitors (icosapent ethyl and rapamycin) as a “pharmaceutical composition” since both have known medicinal qualities (above). The artisan would have been motivated to administer this pharmaceutical composition to a subject with PTSD. The artisan would have expected the pharmaceutical composition to treat PTSD because the pharmaceutical composition is effective in the PTSD animal model (FIFIELD page 458 right col).
It would be obvious to one of ordinary skill in the art to try and promote euthyroiduism because irregular levels could cause undesired side effects.
While the exact dosing schedule is not provided optimizing a dosing schedule is routine experimentation and would be obvious to one of ordinary skill in the art. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.)
This is a provisional nonstatutory double patenting rejection.
Claims 10, 14, 16, 17, 18 and 21, 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 19/409,206 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other .
The application ‘206 claims:
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It would have been prima facie obvious to one of ordinary skill in the art to have modified U.S. Application No. ‘206 to achieve the instant claims. While the exact dosing schedule is not provided optimizing a dosing schedule is routine experimentation and would be obvious to one of ordinary skill in the art. "[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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.) It would be obvious to one of ordinary skill in the art to try and promote euthyroiduism because irregular levels could cause undesired side effects.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 10-11, 14, 16, 17, 18, 19, 20 and 21-23 are rejected.
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/A.A.H./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627