tDETAILED 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 . 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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 30 Oct, 2025 has been entered.
Election/Restrictions
Applicants elected group I (treatment) using SEQ ID 14 without traverse in the reply filed on 29 Oct, 2024.
Claims Status
Claims 1, 2, 26, 38, 54, and 55 are pending.
Claims 1, 2, and 38 have been amended.
Claims 54 and 55 are new.
Withdrawn Objections
The objection to claims 2 and 3 due to non-standard use of a term is hereby withdrawn due to amendment.
The objection to the drawings due to the use of color is hereby withdrawn due to an approved petition to use color drawings.
Withdrawn Rejections
The rejection of claim(s) 1-3, 18, 19, 21-23, and 38 under 35 U.S.C. 103 as being unpatentable over Cherqui (WO 2017165167) in view of Lake et al (Ann. Neurol. (2016) 79 p190-203) and Payne (US 8,283,444) is hereby withdrawn due to amendment.
The rejection of claim(s) 1-3, 18, 19, 21-23, and 38 under 35 U.S.C. 103 as being unpatentable over Cherqui (WO 2017165167, cited by applicants) in view of Lake et al (Ann. Neurol. (2016) 79 p190-203) and Payne (US 8,283,444) is hereby withdrawn due to amendment.
Maintained/Modified 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.
Claims 1, 2, 38, 54, and 55 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.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure(MPEP 2163(3)a(II)). The number of species that describe the genus must be adequate to describe the entire genus; if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers (a) actual reduction to practice, (b) disclosure of drawings or structural chemical formulas, (c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure and (d) representative number of samples.
The issue is if a person of skill in the art would understand what frataxin proteins, defined as a polypeptide with substantially the same activity as the native sequence, even if it has one or more insertions, deletions, substitutions, and modifications (p19, 3d paragraph and p11, 3d paragraph), will retain sufficient activity to be useful in the claimed method.
(a and b) actual reduction to practice and disclosure of drawings or structural chemical formulas: Applicants examples all use a sequence TAT-FXN, presumably SEQ ID 14, note example 4, p33, 3d paragraph, for example. There’s a mention of conservative substitutions (p19, 2nd paragraph through p20, 2nd paragraph).
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure: Applicant is claiming a method of treating a disorder using a frataxin protein, which, as noted above, is the native protein, optionally with one or more insertions, substitutions, deletions, and modifications, so long as the activity is maintained, where the sequence comprises a polypeptide with at least 90% identity to SEQ ID 1 or 2. This is a functional requirement that the polypeptide maintain activity. However, applicant has provided no real discussion as to what portions of the polypeptide can be modified in which way and still maintain activity. A person of skill in the art, armed with applicant’s specification, would not know what sequence/charge/hydrophobicity characteristics are required of any variant to maintain activity. In essence, applicants are describing a critical portion of their invention by function. That is not enough to meet the written restriction requirement.
As of applicant’s priority date, it was not possible to predict if a given molecule bound to a receptor. Lowe (blog “In the pipeline” entry of 7 Sept, 2022) describes an experiment where that was attempted. 39K compounds, including known antibiotics, were screened against E. coli for growth inhibition, finding 218 active compounds (1st page, 3d paragraph). These were computer docked to a set of 296 essential bacterial proteins by multiple docking procedures (1st page, 3d paragraph), along with 100 random inactive compounds (2nd page, 1st paragraph). The number of strong binders predicted were essentially the same between the active compounds and the controls, and out of 142 compound/target interactions previously known, the methodology found only 3 (2nd page, 2nd paragraph). While a given docking program may accurately predict if compound A binds to protein B, it is impossible to a priori know if the prediction is accurate. In other words, several years after applicant’s priority date, it was not possible to predict if a given compound and target bound to each other.
Nor is it possible to modify known sequences to reliably find new compounds. Guo et al (PNAS (2004) 101(25) p9205-9210) looked at the effect of random mutations (title). In a DNA repair enzyme, about one mutation in three killed the activity of the protein, consistent with studies with other proteins (abstract). Yampolsky et al (Genetics (2006) 170 p1459-1472), using a different methodology, found that even conservative substitutions were prone to problems (table 3, p1465, top of page). In other words, unless there is some information known about the binding, mutating the sequence is likely to be detrimental, making it a poor way to generate new compounds.
(d) representative number of samples: Applicants use a single sequence, and mention a second active sequence which is lacking a leader sequence (p11, 3d paragraph). Testi (US 20160060605, cited by applicants) mentions a K147R mutation (corresponding to position 161 of SEQ ID 14). There is no limitation as to the number of mutations of the discussed sequences in the independent claims; the only structural limitations are polypeptide and nucleotide that encodes it. This is a genus that is essentially infinite. Given that it is known that modifications of a sequence are likely to be detrimental to activity, and applicants have provided no information as to what portions of the polypeptide can be modified while maintaining activity, the claims lack written description.
response to applicant’s arguments
Applicant argues that the specification states that modifying the polypeptide will not change its activity, that the specification states that conservative substitutions will not change the activity, gives examples of mutations, and that the spec gives methods to test if a given embodiment will work.
Applicant's arguments filed 30 Oct, 2025 have been fully considered but they are not persuasive.
Applicant argues that the polypeptide maintains activity regardless of mutations. This is simply not credible –this would mean that any polypeptide could be used effectively in applicant’s invention, as they are all equivalent. In addition, the portion of the specification that applicants point to merely defines a derivative as a mutated version of the polypeptide that do not alter the activity, and does not support applicant’s argument that all mutants of the sequence maintain activity.
Applicant argues that conservative substitutions will maintain activity. The portion of the disclosure that applicants point to for support merely defines a conservative substitution as one that “alters, adds, or deletes a single amino acid or a small percentage of amino acids “when the alteration results in the substitution of a chemically similar amino acid.” It does not state that conservative substitutions will maintain activity. Given that the cited prior art (Yampolsky et al) clearly shows that conservative substitutions often abrogate activity, applicant’s argument is not credible. In addition, the claims are not limited to conservative substitutions.
Applicant argues that the specification discloses known point mutations of the sequence. The portion of the disclosure that applicants point to discloses a single position that can be mutated; the same one mentioned in the rejection. There is no evidence of record that a person of skill in the art would know if any other position can be mutated and maintain activity.
Finally, applicant argues that the specification teaches how to test if a given embodiment will work. That means that the claims are enabled for mutated versions of the polypeptide, but does not demonstrate written description.
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.
Claim(s) 1, 2, 26, 38, 54, and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Cherqui (WO 2017165167, cited by applicants) in view of Lake et al (Ann. Neurol. (2016) 79 p190-203), Payne (US 8,283,444), Massodi et al (Molecules 92009) 14 p1999-2015), and Sutton et al (Cancers (April, 2019) 11, 557)
Cherqui discusses treatment of disorders associated with mitochondrial dysfunction by administering a hematopoietic stem cell transfected with human frataxin (abstract). Such cells are presumed to be generating the protein, and so administering them comprises administering the protein. The mitochondrial disease can be Leigh syndrome, and administration of the stem cells corrects neurologic, cardiac, and muscular complications within about 6-12 months of transplantation (paragraph 13).
The difference between this reference and the examined claims is that this reference discusses treating a genus of diseases that include applicant’s claimed disorder, and does not discuss TAT fusion proteins.
Lake et al discusses Leigh syndrome (title). This is the most common pediatric presentation of mitochondrial disease, and is genetically heterogenous, with mutations in either mitochondrial or nuclear genomes (abstract). Leigh syndrome, French Canadian type is one of these, due to a mutation in LRPPRC (p194, 2nd column, 2nd paragraph). This reference states that the disorder treated by the claimed method is a subset of the disorder treated by Cherqui.
Payne et al discusses methods to deliver compounds to mitochondria (title) to treat mitochondrial disorders, such as many of the disorders discussed by Cherqui (column 1, line 20-26). This is done by attaching TAT to the sequences (column 8, line 14-21), with the sequence YGKKRRQRRR given as an example (table 1, columns 7 and 8, bottom of page). Frataxin is explicitly mentioned as a polypeptide that can be used in the invention (column 9, line 20), and an example of this conjugate are made (column 26, line41-53) and tested in an animal model of Freidreich’s ataxia (column 27, line 9-28), one of the disorders mentioned by Cherqui. This reference shows that the disorders of Cherqui can be treated with a TAT-frataxin conjugate.
Massodi et al discuss TAT attached to an elastin like peptide-lactoferin conjugate (abstract). The TAT sequence is MYGRKKRRQRRR (p209, 2nd paragraph), identical with that used by applicants and very similar to that used by Payne.
Sutton et al discusses a sequence comprising TAT attached to the switch II region of DIRAS3 (abstract). A diglycine linker was included between the TAT sequence and the active peptide to prevent interaction between the two motif and to add flexibility to the peptide (5th page, 1st paragraph). This reference discusses diGly linkers in the context of TAT.
Therefore, it would be obvious to use the sequence of Cherqui for the French Canadian variant of Lake et al, as Lake et al teaches this variant is included in the genus of disorders treated by the invention of Cherqui. As this is inclusive, an artisan in this field would attempt this therapy with a reasonable expectation of success.
Furthermore, it would be obvious to use the TAT-frataxin conjugate of Payne to treat the disorders of Cherqui, as Payne states that these can be used to treat mitochondrial disorders, and provide an example with an animal model of one of the disorders of Cherqui. As this is very similar to the therapy of Cherqui, an artisan in this field would attempt this therapy with a reasonable expectation of success.
In addition, it would be obvious to use the TAT sequence of Massodi et al instead of the TAT sequence of Payne, as a simple substitution of one known element for another yielding expected results. As the sequence of Massodi et al comprises the sequence of Payne, an artisan in this field would make this substitution with a reasonable expectation of success.
Finally, it would be obvious to include a Gly-Gly linker between the TAT and the frataxin, as Sutton et al teaches that this will prevent interaction between the two sequences and add flexibility to the peptide. As Sutton et al used this linker in the context of TAT, an artisan in this field would attempt this modification with a reasonable expectation of success.
Cherqui, Lake et al, and Payne render obvious treating Leigh syndrome, French Canadian type with a TAT-frataxin conjugate. Massodi et al renders obvious using the sequence MYGRKKRRQRRR for TAT, and Sutton et al renders obvious adding a diglycine linker between the TAT and the frataxin. Note that this is SEQ ID 14, rendering obvious claims 1, 2, 26, 38, 54, and 55.
response to applicant’s arguments
Applicant argues that Cherqui is not enabled, that there is no reasonable expectation of success, and that the mechanism of action is unexpected.
Applicant's arguments filed 30 Oct, 2025 have been fully considered but they are not persuasive.
Applicant argues that Cherqui is not enabled, because there are no examples with Leigh syndrome, that Leigh syndrome is different than the actual examples of Cherqui, and that Leigh syndrome is given in a laundry list of disorders. As has been noted before, a reference is presumed to be enabled (MPEP 2121(I)). The fact that Cherqui does not provide examples that anticipate applicant’s claims does not mean it is not enabled. The fact that the examples are for a different disorder does not mean it is not enabled. Applicants argue that Leigh syndrome is from a long list of disorders; the list is a relatively short, and all the disorders listed have a common etiology of mitochondrial dysfunction.
Please note that, as Cherqui uses the same active therapeutic (frataxin) to treat a genus that includes the disorder of applicant’s invention, if the reference is not enabled, it is difficult to see how applicant’s invention can be.
Applicant argues there is no expectation of success, as the mechanism of Cherqui does not apply to their invention. The part of the reference that they quote discusses addition of mitochondria with frataxin to the ailing cells. It is difficult to see how this would persuade a person of skill in the art that a method that introduces frataxin to the mitochondria of the ailing cells would be ineffective.
Applicants describe the mechanism of action of the claimed therapy, and argues it is an unexpected result. Unexpected results are compared to the closest prior art (MPEP 716.02(e)), which is Cherqui. That reference treats a genus that includes applicant’s claimed disorder with frataxin, and presumably works by the same mechanism. Also, while working out the mechanism is scientifically important, it is not clear what its significance is to a physician treating a patient (MPEP 716.02(b)(I)). Regardless of the mechanism, based on the cited references, such an individual would expect the therapy to provide a benefit to the patient.
New Rejections
Claim Rejections - 35 USC § 112(a)
The legal basis for rejections under this statute was given above, and will not be repeated here.
Claim 54 is 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.
New claim 54 is a method that uses a polypeptide with at least 98% identity to SEQ ID 14. There is no support for this percent identity to this sequence. While applicants have support for 98% identity with SEQ IDs 1 or 2, the disclosure gives 85, 90, 95, and 99% sequence identity to SEQ ID 14 (p4, 6th paragraph, continues to p5, 1st paragraph). Thus, this limitation constitutes new matter.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRED REYNOLDS whose telephone number is (571)270-7214. The examiner can normally be reached M-Th 9-3:30.
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658