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 .
Election/Restrictions
Applicant’s election without traverse of the following species in the reply filed on 8/21/26 is acknowledged:
Treating MERFF for claim 1;
Diagnosed with MERFF; and
Human as the subject.
Cancellation of claims 11-13 and 21-23 renders moot the fourth species election requirement.
The examiner notes, that for compact prosecution, the claiming of preventing the MERRF mitochondrial myopathy will be examined.
Claim Status
Claims 1, 2, 4, 6-10, 14-16, 19, 20 and 24 are pending.
Claims 3, 5, 11-13, 17, 18, 21-23, 25 and 26 are cancelled.
Claims 1, 2, 4, 6-10, 14-16, 19, 20 and 24 are rejected.
Priority
The instant application, is a Continuation of 16302546 , filed 11/16/2018, now abandoned and having 1 RCE-type filing therein
16302546 is a National Stage entry of PCT/US17/33586 , International Filing Date: 05/19/2017
PCT/US17/33586 Claims Priority from Provisional Application 62338777 , filed 05/19/2016
PCT/US17/33586 Claims Priority from Provisional Application 62351100 , filed 06/16/2016
PCT/US17/33586 Claims Priority from Provisional Application 62395903 , filed 09/16/2016.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 11/24/23, 3/11/25 and 6/3/26 Information Disclosure Statements, except where crossed through, and provides a signed and dated copy of each herewith.
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, 2, 4, 6-10, 14-16, 19, 20 and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MERRF is a genetically inherited disease, see Lorenzoni et al., Arq Neuropsiquiatr 2014;72(10):803-811 (Lorenzoni).
The claimed administered peptide is known to have ameliorative effects on mitochondrial function, including bioenergetics, see Szeto, British Journal of Pharmacology (2014) 171 pp 2029-2050 (Szeto). However, there is no plausible biological basis for such peptide, when administered to a human or other subject in need thereof, to reverse the genetic miscoding cause(s) of MERFF. Compare the instantly claimed administering of a peptide to “Gene therapy for mitochondrial diseases”, 2018, 3 pages, downloaded from Gene therapy for mitochondrial diseases | Max-Planck-Gesellschaft, which uses a “virus delivered the molecular scissor to cut the mutated mtDNA in the targeted tissue,” page 2.
Lacking any plausible basis for the instant administering of the peptide in claims 1, 2, 4, 6-10, 14 for PREVENTING mitochondrial myopathy that is MERRF, a genetically inherited disease, there is a clear lack of possession for such in these claims.
Similarly, lacking any plausible basis for the instant administering of the peptide in claims 15, 16, 19, 20 and 24 for REDUCING THE RISK OF mitochondrial myopathy that is MERRF, a genetically inherited disease, there is a clear lack of possession for such in these claims.
Separately, claim 6 is rejected for lack of possession. Not all signs or symptoms listed in claim 6 are signs or symptoms of MERRF mitochondrial myopathy. This list appears unchanged from the earliest, 4/17/23 claim list, and includes signs/symptoms that are not associated with MERRF. One of these is borborygmi. Please compare with the symptoms found in Lorenzoni et al., Arq Neuropsiquiatr 2014;72(10):803-811 (Lorenzoni), and/or other MERFF specific references, and amend this claim to include only those signs/symptoms that are identified for MERRF.
Claims 1, 2, 4, 6-10, 14-16, 19, 20 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 treating a symptom of MERRF mitochondrial myopathy, does not reasonably provide enablement for preventing MERRF mitochondrial myopathy, nor for reducing the risk of MERRF mitochondrial myopathy. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
MERRF is a genetically inherited disease, see Lorenzoni et al., Arq Neuropsiquiatr 2014;72(10):803-811 (Lorenzoni).
The claimed administered peptide is known to have ameliorative effects on mitochondrial function, see Szeto, British Journal of Pharmacology (2014) 171, pp 2029-2050 (Szeto). However, there is no plausible biological basis for such peptide, when administered to a human or other subject in need thereof, to reverse the genetic miscoding cause(s) of MERFF. Compare the instantly claimed administering of a peptide to “Gene therapy for mitochondrial diseases”, 2018, 3 pages, downloaded from Gene therapy for mitochondrial diseases, Max-Planck-Gesellschaft, which uses a “virus delivered the molecular scissor to cut the mutated mtDNA in the targeted tissue,” page 2.
Given the lack of any plausible basis for the instant administering of the peptide in claims 1, 2, 4, 6-10, 14 for PREVENTING mitochondrial myopathy that is MERRF, a genetically inherited disease, the level of experimentation would be extreme and very unlikely to succeed (here, succeed at least means to “undo” the genetic defect in all relevant cells in the subject that are affected and result in symptoms of MERFF), and as such an clearly undue amount of experimentation would be required. As such, there is a lack of enablement for the preventing aspect of claims 1, 2, 4, 6-10, 14, and they are rejected accordingly.
Similarly, given the lack of any plausible basis for the instant administering of the peptide in claims 15, 16, 19, 20 and 24 for REDUCING THE RISK OF mitochondrial myopathy that is MERRF, a genetically inherited disease, there is a clear lack of possession for such in these claims. Applicant simply has not set forth how administering the claimed peptide could reasonably affect the PAST event of forming a zygote that comprises the genetic defect(s) that result in MERFF, such event being the start of the existence of the subject who will, as a result of the formation of the zygote (including inheritance of the maternal mitochondrial DNA with such defect(s)), later exhibit symptoms of MERFF due to such genetic defect(s) (and potentially also be diagnosed with MERFF). The level of experimentation would be exceedingly extreme and very unlikely to succeed (here, success is interpreted to mean to stop the genetic defect(s) that would cause MERFF from being in the zygote), and as such a clearly undue amount of experimentation would be required. As such, there is a very strong lack of enablement for the preventing aspect of claims 15, 16, 19, 20 and 24, and they are rejected accordingly.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 2, 6-10 and 14 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 20170007663 A1, inventors Szeto and Schiff, published 1/12/17, earliest priority 12/16/13 (SS).
Claim 1 is directed to a method for treating or preventing mitochondrial myopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the peptide D-Arg-2',6'-Dmt-Lys-Phe-NH₂ or a pharmaceutically acceptable salt thereof, thereby resulting in the prevention or treatment of mitochondrial myopathy, wherein the mitochondrial myopathy is myoclonus epilepsy with ragged-red fibers (MERRF).
SS teaches the same peptide having the formula D-Arg-2′,6′-Dmt-Lys-Phe-NH2, in methods and compositions for preventing or treating cognitive dysfunction, Abstract, claims and elsewhere. Claim 1 specifically claims a method for treating or preventing cognitive dysfunction associated with decreased cerebral metabolic rate of oxygen (CMRO) in a mammalian subject in need thereof, comprising administering to the subject a therapeutically effective amount of a peptide represented by the formula D-Arg-2′,6′-Dmt-Lys-Phe-NH.sub.2 or a pharmaceutically acceptable salt thereof, and claim 3 claims the method of claim 1, wherein the cognitive dysfunction is caused by a genetic mitochondrial disorder selected from the group consisting of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonic epilepsy with ragged red fiber (MERRF).
SS therefore anticipates claim 1, and given that SS claim 10 narrows mammalian subject to human, SS anticipates claim 9.
Because SS claim 11 teaches most of the types of administering in instant claim 10, SS anticipates claim 10.
SS also anticipates claim 2 – see paras 0183-0185, claims 6 to 8 – see para 0122, and claim 14 – see para 164.
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) 4 is rejected under 35 U.S.C. 103 as being unpatentable over US 20170007663 A1, inventors Szeto and Schiff, published 1/12/17, earliest priority 12/16/13 (SS), as applied above to claim 1, as evidenced by Lorenzoni et al., Arq Neuropsiquiatr 2014;72(10):803-811 (Lorenzoni).
Claim 1 is rejected above.
Claim 4 adds the requirement that “the subject has been diagnosed as having MERRF.”
In that SS claim 3 specifically claims the method of claim 1, wherein the cognitive dysfunction is caused by a genetic mitochondrial disorder selected from the group consisting of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonic epilepsy with ragged red fiber (MERRF), to meet that the genetic mitochondrial disorder IS MERRF, one of ordinary skill in the art would reasonably expect and assume that the subject had been diagnosed with MERRF, this supported by the evidentiary reference Lorenzoni which teaches characteristics and diagnostic criteria to distinguish MERRF from other mitochondrial genetic diseases/disorders (including MELAS genetic mutations that may be shared in some patients). There would have been a reasonable expectation of success given the routine diagnostic protocols by medical professionals when examining a human subject experiencing symptoms common with MERRF.
Accordingly claim 4 would have been obvious and is rejected under this section.
Claim(s) 1, 2, 4, 6-10, 14 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2014/134562 A1, Travis Wilson, published 9/4/14 (Wilson), in view of Lorenzoni et al., Arq Neuropsiquiatr 2014;72(10):803-811 (Lorenzoni) and Szeto, British Journal of Pharmacology (2014) 171 pp 2029-2050 (Szeto).
Claim 1 is directed to a method for treating or preventing mitochondrial myopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the peptide D-Arg-2',6'-Dmt-Lys-Phe-NH₂ or a pharmaceutically acceptable salt thereof, thereby resulting in the prevention or treatment of mitochondrial myopathy, wherein the mitochondrial myopathy is myoclonus epilepsy with ragged-red fibers (MERRF).
Wilson teaches “methods of preventing, ameliorating or treating disruption of mitochondrial function and symptoms thereof. The methods provide administering aromatic-cationic peptides in effective amounts to prevent, treat or ameliorate the disruption of mitochondrial oxidative phosphorylation in a cell such as that found in a subject suffering from, or predisposed to a mitochondrial disease or disorder,”, Abstract, further teaching, “There are multiple forms of mitochondrial disease. Mitochondrial disease can manifest as a chronic, genetic disorder that occurs when the mitochondria of the cell fails to produce enough energy for cell or organ function. Indeed, for many patients, mitochondrial disease is an inherited condition that runs in families (genetic). Mitochondrial disease is inherited in a number of different ways, for example, autosomal inheritance, mitochondrial DNA (mtDNA) inheritance, and combinations thereof, “ para 0006, and includes specifically reciting the instantly claimed tetrapeptide and its salts in its methods, such as in para 0008, stating in part, “The present technology relates to the prevention, treatment or amelioration of mitochondrial disease and its symptoms, e.g., such as conditions associated with mutations in the SURF 1 gene or POLG gene in mammals or mammalian cells, through administration of therapeutically effective amounts of aromatic-cationic peptides, such as D-Arg-2',6'Dmt-Lys-Phe-NH2, or pharmaceutically acceptable salts thereof, such as acetate salt or trifluoroacetate salt, to subjects in need thereof.”
Claim 1 of Wilson states, “A method for treating a mammalian cell with a disruption of mitochondrial oxidative phosphorylation, wherein the disruption of mitochondrial oxidative phosphorylation is associated with at least one gene mutation, the method comprising: contacting the cell with a therapeutically effective amount of the peptide D-Arg-2',6'-Dmt-Lys-Phe-NH2 or a pharmaceutically acceptable salt thereof, thereby treating or ameliorating the disruption of oxidative phosphorylation in the cell.”
Claim 6 of Wilson states, “A method for treating a mitochondrial disease or disorder associated with at least one gene mutation in a subject in need thereof, the method comprising: administering a therapeutically effective amount of the peptide D-Arg-2',6'-Dmt-Lys-Phe-NH2 or a pharmaceutically acceptable salt thereof, thereby treating or ameliorating at least one symptom of the mitochondrial disease or condition.”
Wilson focuses on “wherein the gene mutation is a SURF 1 gene mutation or a DNA polymerase gamma (POLG) gene mutation,” see claim 5 and elsewhere, however is not so limited in its teachings and statements of uses to treat diseases that disrupt mitochondrial function and symptoms thereof that includes administering the same peptide as instantly claimed. See citations from Wilson above, which clearly demonstrate this.
However, Wilson does not specify from the breadth of its stated treating of diseases that disrupt mitochondrial function and symptoms that one of such diseases is MERRF.
The level of ordinary skill in the art is high.
Lorenzoni teaches that MERRF is a rare mitochondrial disorder in human patients (pages 803 and 804) that manifests in many symptoms (per pages 803-804, “the main manifestation of this group of patients with mitochondrial disease is the presence of myoclonus and epilepsy, other multisystemic alterations can be found as follows: deafness, exercise intolerance, dementia, peripheral neuropathy, short stature, abnormal cardiac conduction, cardiomyopathies, opthalmoparesis, pigmentary retinopathy, and lipoma, among others”), and includes mitochondrial oxidative phosphorylation impairment as an underlying state, also including decreased ATP synthesis, see Figures 1 and 2 and related text. Lorenzoni teaches that “it is estimated that the A8344G mutation remains responsible for over 80% of MERRF patients: mutations T8356C, G8361A and G8363A account for approximately 10%,” page 805, see also Table 1, which includes a mutation associated with MERRF that also is found in Leigh syndrome (this being the noted G8363A mutation).
Thus, Lorenzoni teaches the same type of mitochondrial impairment, reduction of oxidative phosphorylation, in MERRF, that Wilson teaches its peptides treat, including the most noted and evaluated peptide D-Arg-2',6'-Dmt-Lys-Phe-NH2, where such treatment in Wilson improves mitochondrial oxidative phosphorylation across a range of statements and evaluations, however focusing on wherein the gene mutation is a SURF 1 gene mutation or a DNA polymerase gamma (POLG) gene mutation.
More fundamentally, Szeto teaches that the instantly claimed peptide, also identified in the art as SS-31, “SS-31 targets cardiolipin and interacts with cyt c to protect the Met80-haem bond and inhibits peroxidase activity while improving π-π* interaction to promote electron transfer and ATP synthesis. By modulating the interaction between cardiolipin and cyt c, SS-31 favours cyt c as an electron carrier and minimizes its role as a peroxidase (Figure 5),” page 2034. Szeto also teaches that the SS-31 peptide peptide D-Arg-2',6'-Dmt-Lys-Phe-NH2 potently inhibits cardiolipin-induced cyt c peroxidase activity in vitro as well as in isolated mitochondria, indicating that SS-31 can inhibit peroxidase activity of endogenous cyt c in mitochondria, and that the interaction of SS-31 with cardiolipin favours the electron carrier over the peroxidase in cyt c., Id., left column. Page 2033 identifies SS-31 as (D-Arg-2′6′-dimethylTyrLys-Phe-NH2, and states that this is the most studied of “SS peptides”.
Considering these teachings together, one of ordinary skill in the art would reasonably have been motivated to administer the peptide D-Arg-2',6'-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof, to treat the disruption of oxidative phosphorylation in a human subject who has MERRF. Wilson teaches and claims administering this peptide broadly, see claims 1 and 6, elsewhere stating that this is to treat or ameliorate the disruption of mitochondrial oxidative phosphorylation, and focuses its evaluations, including regarding improvements in oxidative phosphorylation, on Leigh syndrome, Alper’s disease, and others that include a mutation of SURF1 or POLG (see also Wilson dependent claims 5, 8, 9). As stated, Lorenzoni teaches the same type of mitochondrial impairment, reduction of oxidative phosphorylation, in MERRF, that Wilson teaches its peptides to improve. Szeto ties the effect of this peptide, referred to as SS-31, to promoting electron transfer and ATP synthesis, these the mechanism and result of effective mitochondrial oxidative phosphorylation.
The motivation derives from a desire to apply a peptide shown and known to have an improving effect on mitochondrial oxidative phosphorylation (this in part based on reducing mitochondrial damage, see Szeto), to a genetic disease, MERFF, that falls within Wilson’s broader statements and also shares with Wilson’s focused-on diseases, as an underlying phenomenon, due to their one or more mitochondrial genetic defects, the reduction of oxidative phosphorylation and consequent lower ATP production. Wilson’s teachings are in the same field of endeavor, and taught administering the same-as-instantly-claimed peptide D-Arg-2',6'-Dmt-Lys-Phe-NH2 or a pharmaceutically acceptable salt thereof, to treat at least one symptom of a mitochondrial disease that involved decreased oxidative phosphorylation in its impaired mitochondria. There were market forces, here a medical need for a severe genetic disease, MERRF, to find a suitable treatment given the severity of its symptoms and progression, see Lorenzoni as to the severity of MERRF and limited treatments. Given respective teachings in Wilson, Lorenzoni and Szeto, differences between the claimed invention and the prior art were encompassed in a principle known in the prior art, this being the use of the peptide D-Arg-2',6'-Dmt-Lys-Phe-NH2 or a pharmaceutically acceptable salt thereof, to treat at least one symptom of a mitochondrial disease that involved decreased oxidative phosphorylation in its impaired mitochondria, which per Szeto also regards the SS-31 peptide peptide D-Arg-2',6'-Dmt-Lys-Phe-NH2 inhibiting cardiolipin-induced cyt c peroxidase activity in vitro as well as in isolated mitochondria, indicating that SS-31 can inhibit peroxidase activity of endogenous cyt c in mitochondria, page 2034 left column. Consequently, one of ordinary skill in the art, in view of the identified market forces and known fundamental effects of the peptide, could have implemented the claimed variation of the prior art, and the claimed variation would have been predictable to one of ordinary skill in the art.
Accordingly, claims 1 and 9 would have been obvious and are rejected under this section.
Wilson teaches administering its peptides for days or weeks, including every week, see paras 124, 125, rendering obvious claim 2.
Claim 4 also would have been obvious and is rejected under this section based on the teachings of diagnosis in Lorenzoni, this reasonably required before treatment, and the bases for rejection of claim 1.
At least because Lorenzino teaches that MERRF symptoms include dementia and this is one of the many signs or symptoms of claim 6, claim 6 would have been obvious and is rejected under this section.
Claims 7 and 8 would have been obvious at least because Lorenzoni teaches that MERRF human subjects have elevated lactic acid, see pages 804 and 807.
Claim 10 would have been obvious given that Wilson teaches administering the same peptide by the following means, from claim 6: orally, topically, systematically, intravenously, subcutaneously, intraperitoneally, or intramuscularly; from para 0023: orally, topically, intranasally, intraperitoneally, intravenously, subcutaneously, or transdermally (e.g., by iontophoresis), and in some embodiments, the aromatic-cationic peptide is administered by an intracoronary route or an intra-arterial route.
Claim 14 also would have been obvious and is rejected under this section at least because Wilson teaches acetate and trifluoroacetate salts of the claimed peptide.
Conclusion
No claim is allowed.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
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