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 the Claims
Claims 4-7, 10-12, and 15-24 are pending. Acknowledgment is made of the addition of claims 21-24 in the reply filed 07/29/2025.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Instant application is a U.S. National Stage Entry of PCT/FR2021/050244, filed 02/11/2021. PCT/FR2021/050244 claims priority of foreign application FR2001355, filed 02/11/2020. Therefore, the effective filing date is 02/11/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/07/2023 and 04/01/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Restriction/Election Requirement
Applicant’s election without traverse of Group III, directed to methods of treating Parkinson’s comprising administering and ROS inhibitors and an anti-synuclein tetracycline, in the reply filed on 07/29/2025 is acknowledged. The elected invention reads on claims 16-24.
Claims 4-7, 10-12, and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/29/2025.
Claim Interpretation
Claim 24 reads “a chimera between 4-hydroxy-anethole trithione and one of the C9 derivatives of doxycycline or minocycline”. The specification states, on page 8 lines 21-24, a “ ‘Chimera’, also referred to as a condensation product, is understood to mean the molecule which is formed after a condensation reaction between 4-OH-anethole trithione (ATX) and one of the derivatives in position 9 of doxycycline or minocycline.” The C9 derivatives of doxycycline and minocycline are defined in the specification, on page 6, as being 9-amino-doxycycline, 9- aminomethyl-doxycycline, 9-amino-4-dedimethylamino-doxycycline, 9-aminomethyl-4-dedimethylaminodoxycycline, 9-amino-minocycline, 9-aminomethyl-minocycline, and the acylated forms of said compounds.
Therefore, claim 24 is interpreted as a method of treating Parkinson’s disease comprising administering a condensation production of 4-OH-anethole trithione and one of the above listed compounds.
Objections to the Claims
Claims 17, 20, 22, and 24 are objected to because of the following informalities:
Claims 17, 20, and 22 read “…anethole trithione or its derivative 4-OH-anethole trithione” (emphasis added) and for clarity should read “…anethole trithione or 4-OH-anethole trithione”.
Claim 24 reads “…4-hydroxy-anethole trithione…”, and to be consistent with the rest of the claims should read “…4-OH-anethole trithione…”.
Appropriate correction is required.
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 16, 18, 19, and 24 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 a method of treating Parkinson’s disease comprising administering anethole trithione, 4-OH-anethole trithione, doxycycline, minocycline, or combinations thereof, does not reasonably provide enablement for a method of treating Parkinson’s comprising administering any molecule that inhibits the production of ROS in combination with any anti-synuclein tetracycline, or with a chimera of 4-OH-trithione and a derivative of doxycycline or minocycline. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}.
The above factors, regarding the present invention, are summarized as follows:
Nature of the invention
The nature of the invention is performance of a method of treating Parkinson’s disease in a patient, comprising administering any molecule that inhibits the production of ROS and any anti-synuclein tetracycline. A method of treating Parkinson’s disease comprising administering a condensation product of 4-OH-anethol trithione and a C9 derivative of doxycycline or minocycline is also described in claim 24.
Breadth of the claims
The breadth of the claims is large and includes a method of treating Parkinson’s disease in a patient comprising administering any molecule that inhibits the production of ROS and any anti-synuclein tetracycline.
State of the prior art
It is taught by Diolez et al. in WO 2017042267 A1 that anethole trithione can be used to treat Parkinson’s disease. It is also taught by Bortolanza et al. (Tetracycline repurposing in neurodegeneration: focus on Parkinson's disease, Journal of Neural Transmission, 2018, Vol. 125, pages 1403-1415) that doxycycline and minocycline can be used in the treatment of Parkinson’s disease. Therefore, the Applicant is enabled for the treatment of Parkinson’s disease comprising administering any of these compounds, or combinations thereof. However, Parkinson’s disease has not been shown to be able to be treated by any combination of a molecule that inhibits the production of ROS and any anti-synuclein tetracycline, as in the instant claims. See In re Hokum, 226 USPQ 353 (ComrPats 1985).
Level of one of ordinary skill in the art
The artisans performing the inventor’s or joint inventor’s method of treating Parkinson’s disease in a patient, comprising administering any molecule that inhibits the production of ROS and any anti-synuclein tetracycline would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
Level of predictability in the art
Synthetic organic chemistry is quite unpredictable. See In re Marzocchi and Horton 169 USPQ at 367 ¶3. Similarly, it is well established that “[T]he scope of enablement varies inversely with the degree of unpredictability of the factors involved, and physiological activity is generally considered to be an unpredictable factor”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Amount of direction provided by the inventor
The invention lacks direction with respect to making and/or using (performing) a method of treating Parkinson’s disease in a patient, comprising administering any molecule that inhibits the production of ROS and any anti-synuclein tetracycline.
Existence of working examples
The disclosure is insufficient to allow extrapolation of the limited examples to enable performing the instantly recited method of treating Parkinson’s disease in a patient, comprising administering any molecule that inhibits the production of ROS and any anti-synuclein tetracycline.
The specification fails to set forth any convincing in vitro and/or in vivo assays corroborating the alleged activity in the treatment of Parkinson’s disease comprising administering any molecule that inhibits the production of ROS and any anti-synuclein tetracycline. The specification only provides examples for neuroprotection comprising administering anethole trithione, 4-OH-anethole trithione, doxycycline, a combination of anethole trithione and doxycycline, and a combination of 4-OH-anethole trithione and doxycycline. No experimental data are provided for the use of minocycline. However, since the prior art teaches that minocycline may be used in the treatment of Parkinson’s disease, it would be assumed that the Applicant is enabled for minocycline and combinations of minocycline with either anethole trithione or 4-OH-anethole trithione.
There are no examples provided of any chimeric molecules of 4-OH-anethole trithione with any C9 derivatives of doxycycline or minocycline, or the testing of said chimeric molecules in the treatment of Parkinson’s disease. There is insufficient disclosure to reasonably conclude that the method of treating Parkinson’s disease in a patient, comprising administering any molecule that inhibits the production of ROS and any anti-synuclein tetracycline, as recited, would contribute to treatment of any the aforementioned diseases. The inventor or joint inventor has neither provided convincing data for any patient population, nor indicated any art recognized correlation between the disclosed data and the breadth of the claim.
Quantity of experimentation needed
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use (perform) the full scope of the claimed invention without undue experimentation. See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
One skilled in the art, such as a medical doctor, would be required to perform hundreds of clinical trials and in vivo or in vitro assays in order to determine which of the infinite combinations of molecules that inhibit the production of ROS and anti-synuclein tetracyclines would be capable of treating Parkinson’s disease. Similarly, one would have to perform the synthesis of chimeric molecules of 4-OH-anethole trithione and C9 derivatives of doxycycline and minocycline, and test the in vivo or in vitro efficacy of said chimeric molecules in the treatment of Parkinson’s disease. Even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404. These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for a method of treating Parkinson’s disease in a patient, comprising administering any molecule that inhibits the production of ROS in combination with any anti-synuclein tetracycline, or with a chimera of 4-OH-trithione and a derivative of doxycycline or minocycline, is clearly justified.
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 16, 18-22, and 24 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.
Regarding claims 20-22, the phrase "or their derivatives" renders the claims indefinite because the claims include elements not actually disclosed (those encompassed by "or their derivatives"), thereby rendering the scope of the claims unascertainable. See MPEP § 2173.05(d).
Claim 24 recites the limitation "the C9 derivatives of doxycycline or minocycline" (emphasis added) in lines 2-3 of the claim. There is insufficient antecedent basis for this limitation in the claim. This rejection would be overcome if the claim read “…and a C9 derivative of doxycycline or minocycline” or listed which C9 derivatives are included in the claim.
The inventor or joint inventor should note that claim 16 is a reach-through claim. The claim attempts to obtain protection for subject matter that is prophetic and/or has yet to be invented. Similarly, the metes and bounds of “a molecule that inhibits the production of reactive oxygen species of mitochondrial origin” are not defined by the claim, the specification does not provide an adequate standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the metes and bounds of the invention. The specification, on page 4, uses open language, such as “such as”, to define molecules that inhibit ROS of mitochondrial origin as anethole trithione and 4-OH-anethol trithione. However, neither the specification, nor the claim, explicitly limits the invention to any specifically disclosed or recited embodiments, including, but not limited to, anethole trithione and 4-OH-anethole trithione. Consequently, the method for the treatment of Parkinson’s disease comprising administering “a molecule that inhibits the production of reactive oxygen species of mitochondrial origin” has been rendered indefinite by the use of the reach-through protocol.
Claims 18, 19, and 21 are rejected as being dependent upon claim 16 and failing to further specify the molecule that inhibits ROS.
The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Rejections - 35 U.S.C. § 112(a), to overcome this rejection.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 24 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 24 recites a composition comprising one compound that is a chimera of 4-OH-anethol trithione and a C9 derivative of doxycycline or minocycline. However, claim 16 requires that the composition contains both a molecule that inhibits the production of ROS and an anti-synuclein tetracycline. The single compound described in claim 24 would not read on claim 16, and therefore fails to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
Claims 16, 18, and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Scheller et al. (US20070191470 A1), as cited by Applicant in the IDS.
Scheller et al. teaches, in claims 8, 25, 27, and 31, a method of treating Parkinson’s disease in a patient comprising administering rotigotine and another active compound, wherein the active compound is selected from minocycline, FK-506, cyclosporin A, or zVAD. Rotigotine is a molecule that inhibits the production of ROS, as evidenced by Radad et al. on page 183 (Rotigotine rescues dopamine neurons, Folia Neuropathologica, 2014, Vol. 52(2), pages 179-186).
MPEP 2131.02 III states: “A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination." Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381, 114 USPQ2d 1250, 1254 (Fed. Cir. 2015) (quoting In re Petering, 301 F.2d 676, 681(CCPA 1962)).” Therefore, one would at once envisage the combination of rotigatine with minocycline, since minocycline is the first compound in a list of only four compounds to be combined with rotigatine in reference claim 27.
Scheller et al. teaches, in claim 10, this method being performed when a patient has received L-DOPA treatment. Paragraph [0025] describes this method to be used in patients who “do not respond, or respond inadequately, to treatment with L-DOPA”, as in instant claim 18.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 16-23 are rejected under 35 U.S.C. 103 as being unpatentable over Diolez et al. (WO 2017042267 A1), and further in view of Bortolanza et al. (cited above), cited by Applicant in the IDS.
Diolez et al. teaches, in claims 1 and 3, a method of treating Parkinson’s disease comprising administering anethole trithione.
It is taught, on page 28 line 18, that the composition should be administered in a range of 2 mg/day to 2000 mg/day, which overlaps with the requirement of instant claim 19 that states that the composition has a daily dosage of 300 to 1200 mg. It is taught, on page 28 line 27, that anethole trithione should be administered in a range of 1 mg/kg/day to 20mg/kg/day, which would be about 60 mg/day to 1200 mg/day, according to Nair et al. (A simple practice guide for dose conversion between animals and human, Journal of Basic and Clinical Pharmacy, 2016, Vol. 7(2), pages 27-31). This range of 60 mg/day to 1200 mg/day of anethole trithione overlaps with instant claim 20, which requires that anethole trithione is present in an amount of 100 mg/day to 400 mg/day per day, and instant claim 22, which requires that anethole trithione is present in an amount of 300 mg/day to 1200 mg/day.
MPEP 2144.05 I states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. Therefore, the amounts of anethole trithione listed in instant claims 19, 20, and 22 are prima facie obvious.
Diolez et al. teaches, on page 20 line 6, that the invention may additionally contain tetracycline.
Diolez et al. fails to teach an embodiment where the anethole trithione is combined with a tetracycline selected from doxycycline or minocycline.
However, Bortolanza et al. teaches, throughout the article, the use of doxycycline or minocycline in the treatment of Parkinson’s disease. It is taught, in the abstract, that tetracyclines are promising candidates for the treatment of Parkinson’s disease, and discusses the repurposing of tetracycline in neurodegeneration. Bortolanza et al. teaches, on page 1406, that doxycycline and minocycline have neuroprotective roles due to their ability to scavenge ROS and free radicals. On page 1406, it states that minocycline and doxycycline have anti-inflammatory effects in the brain by modulating glial cells. Bortolanza et al. teaches, on page 1410, that doxycycline “should be considered an excellent candidate in the development of therapeutic strategies for PD”.
Bortolanza et al. teaches, on page 1410, that “subantibiotic doses” of tetracyclines should be 20-40 mg/day to provide the anti-inflammatory effects without altering bacterial susceptibility to antibiotics. Regarding doxycycline, Bortolanza et al. teaches, on page 1409, that subantimicrobial doses include 20 mg twice daily, which would be 40 mg/day, as in instant claims 20 and 22.
Bortolanza et al. teaches, on page 1404, that the effects of dopamine replacement therapy with L-DOPA, “which is the most efficient treatment of the PD motor symptoms”, decrease with time. Bortolanza et al. suggests that compounds should be found which slow dopaminergic neurodegeneration. Bortolanza et al. then goes on to teach, on page 1409, that doxycycline protected dopaminergic neurons in a model of Parkinson’s disease, displaying that it would useful in patient’s undergoing treatment with L-DOPA, as in instant claim 18.
MPEP 2144.06 I states: “"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)”.
Therefore, since a method of treating Parkinson’s disease with anethole trithione (including the dosage amounts of anethol trithione) and a method of treating Parkinson’s disease with doxycycline (including the dosage amounts of doxycycline) are both taught in the prior art, it would be obvious to combine the two compounds in order to create “a third composition to be used for the very same purpose”.
Conclusion
Claims 16-24 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RILLA M SAMSELL whose telephone number is (703)756-5841. The examiner can normally be reached Monday-Friday, 9-5.
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/R.M.S./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624