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 .
Detailed Action
Filing Receipt
The filing receipt mailed 05/16/2024 states that the instant application is a 371 of PCT/EP2022/066761, filed 06/20/2022, and claimed foreign benefit of EPO 21305849.8, filed 06/21/2021.
The certified copy of the foreign application, received 12/15/2023, supports the instant claims. Therefore the effective filing date is 06/21/2021.
Information Disclosure Statement
The information disclosure statement submitted 12/15/2023 has been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Species Elections
Applicant’s elections with traverse in the reply received 04/01/2026 are acknowledge.
Regarding the traversal, claim 1 is drawn to a generic combination of a monoamine reuptake inhibitor and a potassium-chloride cotransporter type 2 expression-enhancing compound. Alderman (Journal of Clinical Psychopharmacology, Vol. 17, No. 4, 1997, of the record) in its abstract discloses administering the combination of desipramine, a tricyclic antidepressant, with paroxetine, a selective serotonin reuptake inhibitor (SSRI) which has also been shown to have an enhancing effect on KCC2 transporter as reported by Zarei (Iran Biomed J., 2020, 24(5):306-313). Therefore, the arguments regarding the traversal are not persuasive.
The species election is maintained.
At examiner’s discretion, search and examination has been broadened to include fluoxetine, paroxetine, and duloxetine as well as CLP 290, CLP657, CLP257.
Claims 8-9 and 18 are withdrawn from further prosecution as being drawn to non-elected species.
Drawings
The drawings are objected to for the following informality:
Figure 3 contains two “Figures 3A”.
Claim Objections
Claims 10 and 18 recite the limitation "KCC2".
The instant specification on p. 4 defines “Stimulator of potassium-chloride cotransporter type 2” (alternative “KCC2”) as synonymous with “KCC2 expression enhancing compound” (alternatively KEEC).
The instant claims switch from “KEEC” in the parent and dependent claim to “KCC2” without first establishing this synonymous relationship within the claim. Applicant should use one term to avoid confusion.
Multiple Dependency
Claims 32 and 34 are objected to under 37 CFR 1.75(c) as being in improper form because claim 32 is a multiple dependent claim (dependent on claims 1, 31 and canceled claim 16) and claim 34 is dependent on claim 32. See MPEP § 608.01(n).
The MPEP section 608.01(i) states:
(c) One or more claims may be presented in dependent form, referring back to and further limiting another claim or claims in the same application. Any dependent claim which refers to more than one other claim (“multiple dependent claim”) shall refer to such other claims in the alternative only. A multiple dependent claim shall not serve as a basis for any other multiple dependent claim. For fee calculation purposes under § 1.16, a multiple dependent claim will be considered to be that number of claims to which direct reference is made therein. For fee calculation purposes also, any claim depending from a multiple dependent claim will be considered to be that number of claims to which direct reference is made in that multiple dependent claim. In addition to the other filing fees, any original application which is filed with, or is amended to include, multiple dependent claims must have paid therein the fee set forth in § 1.16(j). Claims in dependent form shall be construed to include all the limitations of the claim incorporated by reference into the dependent claim. A multiple dependent claim shall be construed to incorporate by reference all the limitations of each of the particular claims in relation to which it is being considered.”
Claim Rejections
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement
Claims 1-7, 10, 30-32 and 34 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 specific combinations of monoamine reuptake inhibitor and potassium-chloride cotransporter type 2 expression-enhancing compounds (KEEC), does not reasonably provide enablement for all combinations of monoamine reuptake inhibitors and KEEC. 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.
The following Wands factors have been considered: (A) The breadth of the claims, (B) The nature of the invention, (C) The state of the prior art, (D) The level of one of ordinary skill, (E) The level of predictability in the art, (F) The amount of direction provided by the inventor, (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Breadth of the claims
Claim 1 is drawn to a combination of a monoamine reuptake inhibitor and a potassium-chloride cotransporter type 2 expression-enhancing compound.
“Monoamine reuptake inhibitors (MRI)” is not explicitly defined but the specification on p. 2, l. 25-32 states “…serotonin reuptake inhibitor, also called ‘monoamine transporter inhibitor’, or monoamine reuptake inhibitors (‘MRI’) comprising SSRIs, SNRIs, SMS, SNDRI, and TCA,…”. “Serotonin reuptake inhibitor” is defined starting on p. 3, l. 29 of the specification which states “‘Serotonin reuptake inhibitor’, and its synonym ‘Monoamine reuptake inhibitor’, refers herein to any compounds, drugs active agent or pharmaceutically acceptable salt thereof, which acts by inhibiting neuronal reuptake of the neurotransmitter serotonin, and is therefore capable of increasing serotonin levels, and serotoninergic neurotransmission in the brain and the spinal cord.” The specification points to documents listed on p. 4 for examples of SRIs and lists preferred examples on p. 4, l. 18. The listing is exemplary and non-exhaustive.
The term “potassium-chloride cotransporter type 2 expression-enhancing compounds” (alternatively KEEC) is defined on p. 4, l. 25 to be synonymous with “Stimulator of potassium-chloride cotransporter type 2” (alternatively KCC2). The specification states that the terms KEEC and KCC2 are “any compounds, drugs, active agent or pharmaceutically acceptable salt thereof, capable of increasing KCC2 expression, activity or function and reducing the intracellular concentration of chloride ion.” The specification lists examples starting on p. 4, l. 32 and ending p. 6, l. 19. This listing is non-limiting and non-exhaustive.
Therefore, claim 1 is drawn to any combination of any compounds that have been shown to be either a monoamine reuptake inhibitor, or serotonin reuptake inhibitor, and/or any compounds that have been shown to be a KEEC.
Nature of the invention
The invention is drawn to a formulation comprising at least one MRI and one KEEC, as defined above. The specification defines “combination” to be “a formulation wherein the at least one serotonin reuptake inhibitor and the at least one stimulator of KCC2 show synergistic effects in reducing painful sensations induced by peripheral neuropathy, by inflammation or by diabetes, either in vitro and in vivo.” “Synergy” is also defined. See p. 6-7 for full definition.
Additionally, the applicant in their remarks submitted 04/01/2026 states that the “special technical feature that links all the claimed inventions is the synergistic combination of a monoamine reuptake inhibitor and a KCC2 expression-enhancing compound (KEEC) that provides a superior and unexpected therapeutic effect in the treatment of pain.”
State of the prior art
Combinations comprising a KEEC and a MRI are known within the art, as discussed in the art rejections below.
Specific combinations of fluoxetine, paroxetine, duloxetine and amitriptyline with either CLP290 or CLP657 are not disclosed within the art.
Guidance and working examples
The instant application discloses combinations of MRI and KEEC in figures 1A-1B and figure 3, shown below.
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The combinations of Fluoxetine and CLP290, Fluoxetine and CLP657, Fluoxetine PCPZ, Fluoxetine and Kenpaullone, Paroxetine and CLP290, Duloxetine and CLP290, and Amitriptyline and CLP290 are the only combinations disclosed. Additionally, only CLP290 and CLP657 have been shown in combination with a KEEC. CLP257 is not shown within a combination. Amitriptyline is the only compound from its respective genus shown to have efficacy with an MRI. Regarding the single species, the MPEP sec. 2163.05, subsection B. states:
The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
Level of predictability and quantity of experimentation
Considering the above, the instant disclosure is only enabled for the specific combinations disclosed in Fig. 1A-B and Fig. 3 which have the improved effect. The improved effect has not been shown for combinations outside of these, and therefore, the is significant level of unpredictability should one of ordinary skill attempt to combine other MRIs with other KEEC.
Claim Rejections - 35 USC § 112(b)
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.
Indefiniteness
Claims 6, 10, 32, and 34 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 recites the following limitations:
-“molecules of the CLP family”,
-“antipsychotic molecules of the piperazine phenothiazine family”,
-“ATP-competitive inhibitor of glycogen synthase kinase 3 β”,
-“molecules acting through inhibition of the fms-like tyrosine kinase 3 (FLT3), Tropomyosin/Tyrosin receptor kinase B (TrkB) or of Phosphodiesterase 1 (PDE1) or through activation of the sirtuin 1 (SIRT1) or transcient receptor potential cation channel subfamily V member 1 (TRPV1) pathways”.
None of these terms are explicitly defined within the specification. The specification lists exemplary compounds starting on p. 5, l. 13. This listing is non-limiting and applicant does not indicate whether this listing is exhaustive.
Additionally, the use “/” is typically reserved for the use of ratios or for the use of and/or”. The limitation “Tropomyosin/Tyrosin” therefore implies that receptor kinase is of “Tropomyosin and Tyrosin” and “Tropomyosin or Tyrosin”. Because of this ambiguity, the claim is indefinite. Examiner suggest amending the claim to state “Tropomyosin or Tyrosin”.
Dependent on canceled claim
Claims 32 and 34 are dependent from canceled claim 16, and are therefore, rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
“Preferably” and “Such as”
Claim 32 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 32 recites the limitation “for medical use, preferably”. Emphasis by examiner.
The use of the term “preferably” makes the claim indefinite because it implies a scope without definitively limiting the claim. Examiner suggests removing “preferably”.
Similarly, claims 10 and 18 state “such as Amitriptyline”. The use of “such as” is indefinite because it is unclear if “Amitriptyline” is included as a limitation or if it is exemplary.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3 and 30 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Alderman (Journal of Clinical Psychopharmacology, Vol. 17, No. 4, 1997) as evidenced by Zarei (Iranian Biomedical Journal, 24 (5), 2020).
Alderman in its abstract discloses the combine administration of desipramine, a tricyclic antidepressant, with paroxetine. Zarei on p. 398, sec. Results, para. 2 states “Compared to the control, the paroxetine group showed a significant rise (+p <0.05) in KCC2 gene expression.”
The disclosure of Alderman embraces the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
KSR Rationales
The MPEP in section 2143, subsection I gives examples of Rationales for supporting a conclusion of obvious. These rationales are non-exhaustive and include (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Claim(s) 1-5, 30-32 and 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Alderman (cited above), in view of Frampton (CNS Drugs 2007; 21 (7):581-609), Max (N. Engl. J. Med. 1992, Vol. 326, No. 19), Mayo Clinic (Mayo Clinic , Paroxetine (oral route), url= https://www.mayoclinic.org/drugs-supplements/paroxetine-oral-route/description/drg-20067632, accessed 04/23/2026) and NCBI (Desipramine, published 2023, url= https://www.ncbi.nlm.nih.gov/books/NBK470581/, accessed 04/23/2026) and as evidenced by Zarei (cited above).
Discussion of Alderman and Zarei from the 102 rejection is incorporated here.
Alderman does not explicitly discuss or disclose fluoxetine, duloxetine, amitriptyline, CLP290, CLP257, or CLP657. This is addressed by the combination of Frampton, and Max.
Regarding claims 3-4 Frampton is drawn to the compound Duloxetine (title). Frampton on p. 592, sec. 4.2.1 states “No significant between-group differences were reported with regard to the effects of duloxetine 40-120 mg/day and paroxetine 20mg once daily on the primary efficacy measure…”. Frampton continues “No significant between-group differences were reported with respect to the effects of duloxetine 40-120mg/day and fluoxetine 20mg once daily…”. Therefore, one of ordinary skill in the art would find it obvious to switch out paroxetine in the combination taught by Alderman with either fluoxetine or duloxetine as the effects are similar if not the same as taught by Frampton.
Regarding claim 5, Max looks at the effects of desipramine, amitriptyline, and fluoxetine in diabetic neuropathy.
Max in sec. Discussion states “We found that the efficacy of desipramine was similar to that of amitriptyline, the standard therapy for the relief of pain caused by diabetic neuropathy.” Therefore, one of ordinary skill would find it obvious to replace the desipramine of Alderman’s composition with amitriptyline because of the similar properties as reported by Max.
Regarding claim 34, Mayo Clinic and NCBI teach oral dosage forms of paroxetine and desipramine. Additionally, oral dosing is well known within the art and one of ordinary skill would be able to modify the combination to be administered orally.
Regarding claim 32 which is drawn to the combination of claim for medical use, this limitation is considered an intended use which does not change the structure or properties of the claimed combination which is taught within the art. Claim 32 is rejected along with claim 1.
Similarly claim 31, which is drawn to a kit comprising at least one SRI and at least one KCC2, the kit does not impart patentable weight to the combination as it is not a critical component of the claimed combination. Regarding printed matter, the MPEP sec. 2111.5 states:
“To be given patentable weight, the printed matter and associated product must be in a functional relationship. A functional relationship can be found where the printed matter performs some function with respect to the product to which it is associated. [citations omitted].”
Similarly here, the claimed “kit” does not impart a functional relationship to the claimed combination. Therefore, claim 31 is also rejected with claim 1.
The claimed combination of claim 1 is disclosed within the art. Frampton teaches that fluoxetine and duloxetine have similar properties to paroxetine. Max teaches amitriptyline has similar properties to desipramine. Therefore one of ordinary skill in the art would find it obvious to modify the composition of Alderman via the teachings of Frampton and Max to arrive at the instant claims with a reasonable assumption of success. One of ordinary skill would find motivation to make the modifications as the simple substitution of one known element for another can be performed obtain predictable results (KSR B, above).
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUISALBERTO GONZALEZ whose telephone number is (571)272-1154. The examiner can normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.G./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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