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 .
Status of Claims
Claims 1-5 are pending and under examination.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim(s) 1-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural composition of matter without significantly more.
MPEP § 2106 sets forth the Subject Matter Eligibility Test to determine if a claim is directed to patent eligible subject matter. Step 1 asks if a claim is directed to a statutory category of invention. Applicant’s claims are directed to a product; thus, the answer to Step 1 is Yes.
Step 2A, Prong One, asks if a claim recites a product of nature. In this case, Applicant’s Claim 1 is drawn to a pharmaceutical composition comprising: a first active ingredient that is a net antagonist effective amount of D-cycloserine; and a second active ingredient that is S-(+)-mirtazapine, wherein the net antagonist effective amount of D-cycloserine is a dosage ≥500 mg/day to ≤1000 mg/day, and formulated to produce blood levels in excess of 25 µg/mL. Claim 2 is drawn to the pharmaceutical composition of claim 1, wherein the net antagonist effective amount of D-cycloserine is a dosage of equal or greater than 10 mg/kg. Claim 3 is drawn to the pharmaceutical composition of claim 1, further comprising at least one pharmaceutically acceptable carrier or excipient. Claim 4 is drawn to the pharmaceutical composition of claim 1, wherein the composition is a solid or a liquid formulation. Claim 5 is drawn to the pharmaceutical composition of claim 1, wherein the composition is formulated for oral, intravenous, buccal, intraperitoneal, or intramuscular administration.
Thus, the claims do recite products of nature (D-cycloserine). MPEP § 2106.04(b) states that “When a claim recites a nature-based product limitation, examiners should use the markedly different characteristics analysis discussed in MPEP § 2106.04(c) to evaluate the nature-based product limitation and determine the answer to Step 2A.”
This formulation can be formed by mixing the naturally occurring ingredient with an additional active ingredient, further in combination with pharmaceutically acceptable carriers or excipients, which does not change the structure or function of the naturally D-cycloserine. There is no evidence that mixing D-cycloserine with an additional active ingredient, or pharmaceutically acceptable carriers or excipients, leads to a product with a markedly distinct characteristic. Therefore, the claims are considered to be directed to patent ineligible subject matter.
This judicial exception is not integrated into a practical application because either method steps or a physical manifestation of the administration of a composition are needed to show a practical application. The claims are drawn to composition claims rather than method claims and the composition claims do not demonstrate a physical manifestation of the administration of the composition. Therefore, the judicial exception is not integrated into a practical application.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not recite any additional elements beyond the claimed compositions themselves. Therefore, the claims do not recite something significantly more than a judicial exception and are thus deemed patent ineligible subject matter.
MPEP § 2106.04(c)(I) states that “if the nature-based product limitation is not naturally occurring, for example due to some human intervention, then the markedly different characteristics analysis must be performed to determine whether the claimed product limitation is a product of nature exception…”. To perform the markedly different characteristic analysis, MPEP § 2106.04(c)(II) states “The markedly different characteristics analysis compares the nature-based product limitation to its naturally occurring counterpart in its natural state. Markedly different characteristics can be expressed as the product’s structure, function, and/or other properties…”. MPEP section 2106.04 (c-I-B) states “the analysis turns on whether the nature-based product in the claim has markedly different characteristics from its naturally occurring counterpart…”.
In this case, extraction of D-cycloserine only concentrates and portions the naturally occurring compound from Streptomyces bacteria. General extraction from the Streptomyces bacteria does not necessarily result in a markedly distinct change in the naturally occurring compound from the Streptomyces bacteria. Thus, while a solvent extract itself may not be found in the nature, the compounds which are present in the solvent extract, which were extracted from the Streptomyces bacteria are found in nature. The creation of a solvent extract only partitions and concentrates the molecules that are naturally in the Streptomyces bacteria. There is no evidence or reason to expect that any new compounds are formed. The extract itself is a mixture of the naturally occurring compound that is simply soluble in a particular solvent. Thus, while extraction of the compound would separate a portion of the Streptomyces bacteria away from the naturally-occurring ingredient, the result of extraction is still D-cycloserine which is naturally-found in the Streptomyces bacteria; i.e., the compound is not inventive or “man-made.” Thus, D-cycloserine is a naturally occurring compound found in the Streptomyces bacteria. Thus, the claims are drawn to a naturally occurring product. There is no indication that mixing the specified D-cycloserine together with an additional active ingredient such as S- (+)-mirtazapine, and pharmaceutically acceptable carriers or excipients commensurate in scope with the stated claims changes the structure, function, or other properties of the D-cycloserine in any marked way in comparison with the closest naturally occurring counterpart. The closest naturally occurring counterpart for D-cycloserine is a mixture of the naturally occurring compounds of Streptomyces bacteria that are present in the extract. As discussed above, the D-cycloserine mixture is only a mixture of the naturally occurring compounds found in Streptomyces bacteria with synthetic active ingredients, carriers, and excipients, and the mixture appears to maintain its naturally occurring structure and properties and is merely present in the combination. Mixing the D-cycloserine with synthetic ingredients does not amount to significantly more than a combination of judicial exception because mixing a natural product with a synthetic ingredient is well-understood, routine, and conventional in the field. In addition, there is nothing to show that mixing the ingredients in unspecified amounts produces any sort of marked distinction. Thus, the claimed mixture as a whole does not display markedly different characteristics in comparison with the naturally occurring counterparts. Regarding the amounts, there does not appear to be anything that would provide a markedly different change to the structure or function of D-cycloserine. Regarding the form, D-cycloserine is naturally occurring as a solid and can naturally be found in bacteria and thus in fluid as a liquid. Regarding the forms of administration, there is nothing that would change the structure, function, or absorbability of the D-cycloserine. Thus, the claimed mixture as a whole does not display markedly different characteristics in comparison with the naturally occurring counterparts. Therefore, the answer to Step 2A, Prong One, is Yes.
Thus, the analysis must move to Step 2A, Prong Two, which asks if the claim recites additional elements that integrate the judicial exception into a practical application. As discussed in MPEP § 2106.04(d)(2) this evaluation is performed by identifying whether there are additional elements recited in the claim beyond the judicial exception and evaluating these additional elements to determine whether the claim as a whole integrates the exception into a practical application. In this case, the claims are directed to composition with synthetic ingredients in addition to the natural product. Thus, the answer to Step 2A, Prong Two, is No.
The analysis must then move to Step 2B which asks if claims recite additional elements that amount to significantly more than the judicial exception. MPEP § 2106.05 states that this evaluation is performed by “Evaluating additional elements to determine whether they amount to an inventive concept requires considering them both individually and in combination to ensure that they amount to significantly more than the judicial exception itself.” In this case, the additional element in the claims is the combination of the D-cycloserine, an active synthetic ingredient, and synthetic carriers and excipients. However, MPEP § 2106.05(d) states that well-understood, routine, and conventional activities are not sufficient to show that the claims amount to significantly more than the judicial exception. It is well understood, routine and conventional to use alternative active ingredients in combination with other active ingredients and pharmaceutically acceptable carriers and excipients. Thus, the answer to Step 2B is No. Therefore, the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112
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 1-5 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 D-cycloserine having a net antagonist effective amount on NMDA receptors, does not reasonably provide enablement for the full-scope of antagonist activity on any and all receptors. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the Invention: The nature of the invention is complex in that the claims are drawn to a pharmaceutical composition comprising: a first active ingredient that is a net antagonist effective amount of D-cycloserine; and a second active ingredient that is S-(+)-mirtazapine, wherein the net antagonist effective amount of D-cycloserine is a dosage ≥500 mg/day to ≤1000 mg/day, and formulated to produce blood levels in excess of 25 µg/mL.
However, the Applicant has not demonstrated that D-cycloserine acts as an antagonist for any molecular target other than the NMDA receptor.
Breadth of the Claims: The claims are broad in that the claims recite a composition comprising: a first active ingredient that is a net antagonist effective amount of D-cycloserine; and a second active ingredient that is S-(+)-mirtazapine, wherein the net antagonist effective amount of D-cycloserine is a dosage ≥500 mg/day to ≤1000 mg/day, and formulated to produce blood levels in excess of 25 µg/mL, wherein the D-cycloserine is an antagonist for any and all molecular targets. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the Specification and Existence of Working Examples: The specification describes D-cycloserine working as an antagonist at the NMDA receptor at blood concentration greater than 25 µg/mL.
However, no working examples are given showing D-cycloserine working as an antagonist for any other molecular target. While it is noted that the applicant has shown data for D-cycloserine working as an NMDA receptor antagonist at a blood concentration greater than 25 µg/mL, the applicant is not enabled for D-cycloserine working as an antagonist for any and all molecular targets.
Predictability and State of the Art: The state of the art at the time the invention was made was unpredictable and underdeveloped. It is known in the art that D-cycloserine is an NMDA receptor partial agonist as taught by Difede, J. [“D-cycloserine Augmentation of Exposure Therapy for Post-Traumatic Stress Disorder: A Pilot Randomized Clinical Trial”, Neuropsychopharmacology, Vol. 39, pp. 1052–1058 (Year: 2014)].
It is also known in the art that partial agonists at certain concentrations can act as antagonists, relative to another more potent agonist. This concept is taught by Science Direct. [Partial Agonism, [online], [retrieved on 4/30/2026]. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/partial-agonism (Year:2018)].
However, it is not understood in the art that a compound or generic class of compounds known to act as an antagonist at a given molecular target, such as the instant NMDA receptor, would also be known to act as an antagonist at any and all molecular targets wherein antagonism is mechanistically possible. In an alternative explanation, it is not understood that another molecular target other than the NMDA receptor, that is known to be antagonized by its respective antagonists, would also be antagonized by a known antagonist of NMDA receptors, such as the instant D-cycloserine. Roy, Kunal, and Arkaprava Banerjee. Activity Cliffs. (SpringerBriefs in Molecular Science, Cham, Springer Nature Switzerland, 2025. Accessed 30 April. 2026) supports this concept by teaching that changes in compound structure can result in unexpected and unpredictable activity, even across species of compounds that are structurally similar (See Page 37; 3.1). This elucidates the high degree of specificity between compound structure and activity, and further solidifies the concept that one compound cannot be expected to act as an antagonist across such a wide range of molecular targets, as instantly claimed by the Applicant.
Amount of Experimentation Necessary: The quantity of experimentation necessary to carry out the claimed invention is high, as the skilled artisan could not rely on the prior art or instant specification to teach D-cycloserine as a net antagonist across the full-scope of molecular targets.
In order to carry out the claimed invention, one of ordinary skill in the art would have to determine that D-cycloserine acts as an antagonist at any and all molecular targets, at a blood concentration greater than 25 µg/mL . In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1-5 are not considered to be fully enabled by the instant specification.
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 1-5 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.
The metes and bounds of claims 1-5 are rendered uncertain by the phrase “formulated to produce blood levels in excess of 25 µg/mL” in independent claim 1, lines 6-7, because it is not clear what the Applicant intends to claim as being formulated. For example, does the Applicant intend to administer the dose to a subject by a certain route of administration to arrive at the claimed blood levels? Or does the Applicant intend to modify the overall composition in an alternative way to arrive at the claimed blood levels? The lack of clarity renders the claims indefinite since the resulting claims do not clearly set forth the metes and bounds of the patent protection desired.
The metes and bounds of claim 2 is rendered uncertain by the phrase “wherein the net antagonist effective amount of D-cycloserine is a dosage of equal or greater than 10 mg/kg” in claim 2, lines 1-3, because it is not clear what the Applicant intends to claim as a range for dosing D-cycloserine, as there is no upper bound in claim 2, whereas independent claim 1 sets a lower bound at 500 mg/day and an upper bound at 1000 mg/day. As the weight of the potential subject to receive this composition is unknown, the dose of equal or greater than 10 mg/kg could exceed the upper limit of 1000 mg/day, and similarly fall below the lower limit of 500mg/day, as recited in independent claim 1.
Examiner requests that consistency is maintained with the units in claiming levels and amounts, to avoid required extrapolation between weight based and non-weight-based numbers, when no specific subject with determined weight is disclosed.
The lack of clarity renders the claims indefinite since the resulting claims do not clearly set forth the metes and bounds of the patent protection desired.
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.
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.
Claim(s) 1-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Heresco-Levy, U., et. al. (US Patent Publication US 2014/0018349 A1; Published 1/16/2014).
Heresco-Levy teaches a composition for treatment of depression comprising D-cycloserine, wherein the dose of the D-cycloserine is 1000mg/day administered orally (See Page 1; Abstract and Page 14; Claim 55), which reads on Applicant’s claim 1. Further, claim 1 of Heresco-Levy teaches D-cycloserine at a dosage of from about 500 mg/day to 1200 mg/day (reading on Applicants range in claim 1), and that a second active ingredient for the treatment of depression can be included in the composition along with D-cycloserine (See Page 13; Claim 1), wherein the second active ingredient for the treatment of depression can be mirtazapine (See Page 5; Paragraph 0085), and further teaches the randomized administration of D-cycloserine (See Page 10; Paragraph 0169), to patients already receiving mirtazapine for treatment of depression(See Page 10; Paragraph 0173).
Heresco-Levy further teaches that the orally administered composition is in a solid formulation as a pill (See Page 14, Claim 33) (which reads on claim 4), and contains pharmaceutically acceptable carriers or excipients (see Page 6; Paragraph 0107)(which reads on claim 3).
Heresco-Levy does not explicitly teach that the amount of D-cycloserine (1000 mg/day) administered is a net antagonist effective amount, that this amount is equal to or greater than 10 mg/kg, or that it results in blood levels in excess of 25 micrograms/mL.
However, Heresco-Levy teaches that low doses of D-cycloserine results in agonist activity, while higher doses result in antagonist activity (See Page 2; Paragraph 0013). This teaching, provides a result-effective variable from which one having ordinary skill in the art would be expected to optimize the amount of D-cycloserine administered to a given subject to achieve the established result of NDMA antagonism (MPEP 2144.05).
Further, absent of a specific subject of administration from which to base these limitations on, Heresco-Levy teaching administration of Applicant’s claimed net antagonist effective amount of 1000 mg of D-Cycloserine would intrinsically result in the blood levels in excess of 25 micrograms/mL, as well as intrinsically be equivalent to or greater than 10mg/kg, and act as a net antagonist at the NMDA receptor, in a given subject.
Examiner acknowledges that Heresco-Levy does not directly teach a composition comprising D-cycloserine and mirtazapine, wherein the net antagonist effective amount of D-cycloserine is a dosage ≥500 mg/day to ≤1000 mg/day, and formulated to produce blood levels in excess of 25 µg/mL.
However, it would have been obvious to modify the teachings of Heresco-Levy before the effective filing date to provide the instantly claimed invention. Heresco-Levy provides adequate teaching, suggestion, and motivation to one having ordinary skill in the art, before the Applicant’s effective filing date, to create a composition comprising D-cycloserine at a dose of 1000 mg/day, intrinsically resulting in a dose of 10 mg/kg in a given subject, (which would intrinsically result in blood levels greater than 25 micrograms/mL) by combining D-cycloserine with mirtazapine and pharmaceutical acceptable carriers or excipients, in a solid or liquid formulation, intended for oral administration.
One skilled in the art would have been motivated and have had reasonable expectation of success to use the teachings of Heresco-Levy to provide the instant composition because Heresco-Levy teaches D-cycloserine at an oral dose of 1000mg/day, intrinsically resulting in a dose of 10mg/kg and a blood concentration of 25 µg/mL intrinsically resulting in a net antagonist activity at the NMDA receptor, in a composition with pharmaceutically acceptable carriers and excipients, for the treatment of depression, and teaches that a secondary active ingredient also useful for treatment of depression is included in the composition, and that the second active ingredient can be mirtazapine, further taught to be one of a select list of medication that patients were already talking for treatment of depression prior to receiving D-cycloserine for treatment of depression.
Therefore, it would have been obvious to one having ordinary skill in the art, before the Applicant’s effective filing date, to use these teachings to provide a composition comprising D-cycloserine at a dose of 1000 mg/day, intrinsically resulting in a dose of 10mg/kg and a blood concentration of 25 µg/mL intrinsically resulting in a net antagonist activity at the NMDA receptor, in combination with mirtazapine, and wherein the composition includes pharmaceutical acceptable carriers or excipients, is in a solid or liquid formulation, intended for oral administration.
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.
(OF NOTE: The following nonstatutory double patenting rejections are NON-PROVISIONAL)
Claims 1-5 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 4, and 5, of U.S. Patent No.11,969,431B2 in view of Heresco-Levy, U., et. al. (US Patent Publication US 2014/0018349 A1; Published 1/16/2014).
Although the claims are not identical, they are not patentably distinct from one another because the claims of 11,969,431B2 are also drawn to the same compounds and composition of the instant application, with comparable and obvious limitations such as formulation modifications, using the claimed composition in a method, and obvious routes of administration of the composition. The 11,969,431B2 claims 1, 2, 4 and 5 are all drawn to a method of using the instant composition. However, these claims anticipate the instant composition, as using a composition in a method requires the composition itself. Notable limitations in the instant application not found in 11,969,431B2 include, formulation modifications such as a pharmaceutically acceptable carrier or excipient, as recited in instant claim 3, a solid or a liquid formulation, as recited in claim 4, and the composition being formulated for oral, intravenous, buccal, intraperitoneal, or intramuscular administration, as recited in claim 5. Further, the instant Application requires that the net antagonist effective amount of D-cycloserine is further a dosage of equal or greater than 10 mg/kg, which is not recited in 11,969,431B2. However, these limitations are not patentably distinct, as explained further below.
Heresco-Levy teaches a composition for treatment of depression comprising D-cycloserine, wherein the dose of the D-cycloserine is 1000mg/day administered orally (See Page 1; Abstract and Page 14; Claim 55), which reads on Applicant’s claim 1. Further, claim 1 of Heresco-Levy teaches D-cycloserine at a dosage of from about 500 mg/day to 1200 mg/day (reading on Applicants range in claim 1), and that a second active ingredient for the treatment of depression can be included in the composition along with D-cycloserine (See Page 13; Claim 1), wherein the second active ingredient for the treatment of depression can be mirtazapine (See Page 5; Paragraph 0085), and further teaches the randomized administration of D-cycloserine (See Page 10; Paragraph 0169), to patients already receiving mirtazapine for treatment of depression(See Page 10; Paragraph 0173).
Heresco-Levy further teaches that the orally administered composition is in a solid formulation as a pill (See Page 14, Claim 33) (which reads on claim 4), and contains pharmaceutically acceptable carriers or excipients (see Page 6; Paragraph 0107) (which reads on claim 3).
Heresco-Levy does not explicitly teach that the amount of D-cycloserine (1000 mg/day) administered is a net antagonist effective amount, that this amount is equal to or greater than 10 mg/kg, or that it results in blood levels in excess of 25 micrograms/mL.
However, Heresco-Levy teaches that low doses of D-cycloserine results in agonist activity, while higher doses result in antagonist activity (See Page 2; Paragraph 0013). This teaching, provides a result-effective variable from which one having ordinary skill in the art would be expected to optimize the amount of D-cycloserine administered to a given subject to achieve the established result of NDMA antagonism (MPEP 2144.05).
Further, absent of a specific subject of administration from which to base these limitations on, Heresco-Levy teaching administration of Applicant’s claimed net antagonist effective amount of 1000 mg of D-cycloserine would intrinsically result in the blood levels in excess of 25 micrograms/mL, as well as intrinsically be equivalent to or greater than 10mg/kg, and act as a net antagonist at the NMDA receptor, in a given subject.
Examiner acknowledges that Heresco-Levy does not directly teach a composition comprising D-cycloserine and mirtazapine, wherein the net antagonist effective amount of D-cycloserine is a dosage ≥500 mg/day to ≤1000 mg/day, and formulated to produce blood levels in excess of 25 µg/mL.
However, it would have been obvious to modify the teachings of Heresco-Levy before the effective filing date to provide the instantly claimed invention. Heresco-Levy provides adequate teaching, suggestion, and motivation to one having ordinary skill in the art, before the Applicant’s effective filing date, to create a composition comprising D-cycloserine at a dose of 1000 mg/day, intrinsically resulting in a dose of 10 mg/kg in a given subject, (which would intrinsically result in blood levels greater than 25 micrograms/mL) by combining D-cycloserine with mirtazapine and pharmaceutical acceptable carriers or excipients, in a solid or liquid formulation, intended for oral administration.
One skilled in the art would have been motivated and have had reasonable expectation of success to use the teachings of Heresco-Levy to provide the instant composition because Heresco-Levy teaches D-cycloserine at an oral dose of 1000mg/day, intrinsically resulting in a dose of 10mg/kg and a blood concentration of 25 µg/mL intrinsically resulting in a net antagonist activity at the NMDA receptor, in a composition with pharmaceutically acceptable carriers and excipients, for the treatment of depression, and teaches that a secondary active ingredient also useful for treatment of depression is included in the composition, and that the second active ingredient can be mirtazapine, further taught to be one of a select list of medication that patients were already talking for treatment of depression prior to receiving D-cycloserine for treatment of depression.
Therefore, it would have been obvious to one having ordinary skill in the art, before the Applicant’s effective filing date, to use these teachings to provide a composition comprising D-cycloserine at a dose of 1000 mg/day, intrinsically resulting in a dose of 10mg/kg and a blood concentration of 25 µg/mL intrinsically resulting in a net antagonist activity at the NMDA receptor, in combination with mirtazapine, and wherein the composition includes pharmaceutical acceptable carriers or excipients, is in a solid or liquid formulation, intended for oral administration.
It would have been prima facie obvious to one skilled in the art to arrive at the Applicant’s instant claims, in view of the claims of U.S. Patent No.11,969,431B2, and Heresco-Levy, U., et. al. (US Patent Publication US 2014/0018349 A1; Published 1/16/2014).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OROD MOTEVALLI whose telephone number is (571)272-6026. The examiner can normally be reached Monday - Friday 10:00AM - 6:00PM.
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/OROD MOTEVALLI/ Examiner, Art Unit 1628
/AMY L CLARK/ Supervisory Patent Examiner, Art Unit 1628
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