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
Request for Continued Examination Under 37 CFR 1.1143
A request for continued examination (RCE) 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 mailed on May 4, 2026 has been entered.
Claims 1 and 24 have been amended. Claims 1, 23, 24 and 31-42 are pending in the instant application.
Claims 1, 23, 24 and 31-42 have been examined on the merits as detailed below:
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Response to Arguments
Applicant's Amendment and Response filed May 4, 2026 has been considered. Communications, rejections and/or objections not reiterated from the previous Office Action mailed December 3, 2025 are hereby withdrawn. Any arguments addressing said rejections and/or objections are moot. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Claim Rejections - 35 USC § 103
In the previous Office Action mailed December 3, 2025, claims 1, 23 and 31-42 were rejected under 35 U.S.C. 103 as being obvious over YINGXIAO SHI ET AL. NATURE MEDICINE, Vol. 24, No. 3, 5 February 2018 (2018-02-05), pages 313-325, plus Supplementary Data in view of Xue-Hai Liang et al. (Molecular Therapy Vol. 25 No 9 September 2017, pages 2075-2092) and evidenced by Geary et al. (Clin Pharmacokinet (2015) 54:133-146) and Shemesh et al. (Molecular Therapy: Nucleic Acids Vol. 9 December 2017, pages 34-47). This rejection is withdrawn in view of Applicant’s Amendment to the claim 1 filed May 4, 2026.
Applicant’s Amendment to the claims filed May 4, 2026 necessitated a new grounds of rejection(s) as presented below:
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, 23 and 31-42 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. This is a written description rejection.
The following quotation from section 2163 of the Manual of Patent Examination Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirement for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice..., reduction to drawings..., or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Thus, when a claim covers a genus of inventions, the disclosure must provide written support for the entire scope of the genus. Support for a genus is generally found where the Applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed and that applicant was in possession of the claimed genus.
The claims are drawn to a single stranded antisense oligonucleotide (ASO) that suppresses the expression of a PIKFYVE encoded by the sequence of SEQ ID NO: 137,wherein the ASO comprises, from 5' to 3':a 5' wing segment consisting of 5 2'-O-methoxyethyl nucleosides linked by internucleoside linkages, wherein (i) each of the internucleoside linkages within the 5' wing segment is a phosphorothioate linkage or a phosphodiester linkage, wherein (ii) the 5' wing segment comprise at least one phosphorothioate linkage and at least one phosphodiester linkage, and (iii) each nucleoside in the 5' wing segment comprises a DNA nucleobase; a gap segment consisting of 10 deoxynucleosides linked by internucleoside linkages, wherein each internucleoside linkage within the gap segment is a phosphorothioate linkage, wherein the internucleoside linkage between the 5' wing segment and the gap segment is a phosphorothioate linkage or a phosphodiester linkage; and a 3' wing segment consisting of 5 2'-O-methoxyethyl nucleosides linked by internucleoside linkages, wherein (i) each of the internucleoside linkages within the 3' wing segment is a phosphorothioate linkage or a phosphodiester linkage, wherein (ii) the 3' wing segment comprise at least one phosphorothioate linkage and at least one phosphodiester linkage, wherein (iii) the internucleoside linkage between the gap segment and the 3' wing segment is a phosphorothioate linkage or a phosphodiester linkage, and (iv) each nucleoside in the 3' wing segment comprises a DNA nucleobase; and a method treating a subject having a neurological or neurodegenerative disease in need of treatment thereof, comprising: administering a therapeutically effective amount of said single stranded antisense oligonucleotide. As discussed below, there is insufficient written description for the single stranded antisense oligonucleotides encompassed by the claims.
The instant Specification provides examples at Table 2 which discloses MOE gapmers of the disclosure. For example, see:
Table 2. PIKFYVE Antisense Oligonucleotide Sequences (ASOs). (Gapmer design: 5'- five 2'-methoxyethylribose nucleotides - ten DNA nucleotides - five 2'-methoxyethylribose nucleotides - 3'; /i2MOErN/ = 2’-methoxyethylribose nucleotide; A, C, T, G = adenine, cytosine, thymine, guanosine, respectively; * = phosphorothioate linkages) (Note that the following Table provide 2’MOE wings, however, alternative wings comprising 2’-OMe, LNA etc. are contemplated)
NOTE: The Gapmers that suppress PIKFYVE disclosed in the present invention at Table 2 consist of single stranded antisense oligonucleotide (ASOs) with only phosphorothioate linkages. However, the claims recite and require that the 5’ and 3’ wing segments include at least one phosphorothioate linkage and at least one phosphodiester linkage. There is insufficient written description of the single stranded ASOs encompassed by the claims as the instant Specification does not disclose a single species which carries out the functionality of the claimed invention.
The written description requirement for claims that a single stranded antisense oligonucleotide that suppresses the expression of a PIKFYVE, wherein the 5’ and 3’ wing segments of the antisense oligonucleotide include at least one phosphorothioate linkage and at least one phosphodiester linkage is not met because the claims encompass a genus of single stranded antisense oligonucleotides which are not adequately described.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The Specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
To satisfy the written description requirement, an applicant must describe the invention is such a way as to convey to one skilled in the art that applicant had the invention in his possession when the application was filed. Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc). In cases such as the instant application where a genus is claimed, the specification must contain “either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350. However, the written description requirement for claims that recite a single stranded antisense oligonucleotide that suppresses the expression of a PIKFYVE, wherein the 5’ and 3’ wing segments of the antisense oligonucleotide include at least one phosphorothioate linkage and at least one phosphodiester linkage in each nucleoside in each wing is not met.
The prior art teaches and exemplifies a single stranded antisense oligonucleotide that suppresses the expression of a target gene wherein the 5’ and 3’ wing segments of the antisense oligonucleotide include at least one phosphorothioate linkage and at least one phosphodiester linkage. See WO 2015/153800 - Embodiment #4; claim #4; and Tables 35, 45, 50, for example. See “Backbone Chemistry” in the Tables.
The entire genus of single stranded antisense oligonucleotide that suppresses the expression of a PIKFYVE, wherein the 5’ and 3’ wing segments of the antisense oligonucleotide include at least one phosphorothioate linkage and at least one phosphodiester linkage that function as claimed does not exist in the instant application. That is, adequate written description support does not exist to practice the full scope of the invention claimed. The specification nor the prior art discloses neither a representative number of species oligonucleotides nor any structure/function correlation that would enable one of skill to immediately envision the genus of single stranded ASOs that suppresses the expression of a PIKFYVE, wherein the 5’ and 3’ wing segments of the ASOs include at least one phosphorothioate linkage and at least one phosphodiester linkage required to practice the full scope of the invention.
As stated above, the MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic claim. Given the breadth of the claims, the Specification lacks sufficient variety of species to reflect the variance in the genus.
In conclusion, the Specification and the prior art as filed does not provide sufficient descriptive support for the myriad of single stranded antisense oligonucleotides embraced by the claims. For the reasons discussed above, the 35 USC § 112 rejection for written description is applicable.
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.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 23 and 31-42 are rejected under 35 U.S.C. 103 as being obvious over YINGXIAO SHI ET AL. (NATURE MEDICINE, Vol. 24, No. 3, 5 February 2018 (2018-02-05), pages 313-325, plus Supplementary Data) (submitted and made of record on the IDS filed February 27, 2024) in view of WO 2015/153800 A2.
The claims are drawn to a single stranded antisense oligonucleotide (ASO) that suppresses the expression of a PIKFYVE encoded by the sequence of SEQ ID NO: 137, wherein the ASO comprises, from 5' to 3':a 5' wing segment consisting of 5 2'-O-methoxyethyl nucleosides linked by internucleoside linkages, wherein (i) each of the internucleoside linkages within the 5' wing segment is a phosphorothioate linkage or a phosphodiester linkage, wherein (ii) the 5' wing segment comprise at least one phosphorothioate linkage and at least one phosphodiester linkage, and (iii) each nucleoside in the 5' wing segment comprises a DNA nucleobase; a gap segment consisting of 10 deoxynucleosides linked by internucleoside linkages, wherein each internucleoside linkage within the gap segment is a phosphorothioate linkage, wherein the internucleoside linkage between the 5' wing segment and the gap segment is a phosphorothioate linkage or a phosphodiester linkage; and a 3' wing segment consisting of 5 2'-O-methoxyethyl nucleosides linked by internucleoside linkages, wherein (i) each of the internucleoside linkages within the 3' wing segment is a phosphorothioate linkage or a phosphodiester linkage, wherein (ii) the 3' wing segment comprise at least one phosphorothioate linkage and at least one phosphodiester linkage, wherein (iii) the internucleoside linkage between the gap segment and the 3' wing segment is a phosphorothioate linkage or a phosphodiester linkage, and (iv) each nucleoside in the 3' wing segment comprises a DNA nucleobase; and a method treating a subject having a neurological or neurodegenerative disease in need of treatment thereof, comprising: administering a therapeutically effective amount of said single stranded antisense oligonucleotide.
YINGXIAO SHI teaches two single stranded antisense oligonucleotides (ASOs) that suppress the expression of PIKFYVE, for the treatment of amyotrophic lateral sclerosis (ALS) (Results, page 321, left column; Figure 6d, page 322). The ASOs are 20 nucleotides long and the internucleoside linkages are modified with phosphorothioate linkages. The ASOs are gapmers with a 5' and a 3' wing of 5 nucleotides each, whose sugar moieties are 2'-O-methoxyethyl (2'-OMe) modified, and a central gap segment of 10 deoxynucleosides, with phosphorothioate linkages within the gap segment. The sequences of the two ASOs are identical to SEQ ID NO. 136 and 9 of the present invention. See YINGXIAO SHI Supplementary data Table 4, page 53, PIKFYVE ASO 1 and PIKFYVE ASO 2.
The administration of the ASOs of YINGXIAO SHI rescued the ex vivo motor neurons of ALS patients (Results, page 321). The ALS patient of the YINGXIAO SHI study is haplosufficient for the C9ORF72 gene. The haplosufficiency results in a 50% greater reduction in C9ORF72 protein activity. See Supplementary Figure 4J. The C9ORF72 gene product comprises a dipeptide repeat resulting from a (GGGGCC)n expansion. The dipeptide repeat is cytotoxic. It is noted that the ALS disorder taught and disclosed by YINGXIAO SHI is associated with neuronal hyperexcitability and aberrant endosomal and lysosomal trafficking.
YINGXIAO SHI does not teach single stranded ASOs, wherein the 5’ and 3’ wing segments of the ASOs include at least one phosphorothioate linkage and at least one phosphodiester linkage. Also, YINGXIAO SHI does not teach ASOs, wherein each nucleoside in the 5’ and 3’ wing segments comprises a DNA nucleobase.
WO 2015/153800 teaches single stranded ASOs, wherein the 5’ and 3’ wing segments of the ASOs include at least one phosphorothioate linkage (s) and at least one phosphodiester linkage (o). See Embodiment #4; claim #4; and Tables 35, 45, 50, for example. See “Backbone Chemistry” in the Tables. Each of the internucleoside linkages within the 5’ and 3’ wing segments is a phosphorothioate linkage or phosphodiester linkage.
WO 2015/153800 also teaches ASOs, wherein each nucleoside in the 5’ and 3’ wing segments comprises a DNA nucleobase. See Tables 35, 45, 50, for example. See “Sequence” in the Tables.
Also, WO 2015/153800 teach:
In certain embodiments, a 2'-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (e.g., uracil); and
An antisense compound is identical to the sequence disclosed herein if it has the same nucleobase pairing ability. For example, a RNA which contains uracil in place of thymidine in a disclosed DNA sequence would be considered identical to the DNA sequence since both uracil and thymidine pair with adenine.
Before the effective filing date of the claimed invention, a single stranded antisense oligonucleotide (ASO) that suppresses the expression of a PIKFYVE encoded by the sequence of SEQ ID NO:137 of the present invention was routinely used in the art for the purpose of treating a subject having a neurological disease, such as ALS as taught and suggested by YINGXIAO SHI.
Before the effective filing date of the claimed invention, ASOs comprising the particular 5’ and 3’ chemical modifications, including those recited for the wing and gap segments was known and routinely used in the art as taught and suggested by WO 2015/153800.
A person of ordinary skill in the art would have been motivated and expected reasonable success to modify the ASO of YINGXIAO SHI to include wherein the 5’ and 3’ wing segments of the ASO include at least one phosphorothioate linkage and at least one phosphodiester linkage as motivated by WO 2015/153800 for the purpose of combining high nuclease resistance and cellular uptake of phosphorothioate linkages with the superior binding affinity and lower toxicity of phosphodiester linkages.
The combination of the prior art of YINGXIAO SHI in view of WO 2015/153800 renders the present claims unpatentable because a person of ordinary skill in the art would have found the instant invention prima facie obvious.
Markush Rejection
Claim 23 is rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The claims are directed to a multitude of single stranded antisense oligonucleotides with no common searchable core. The dozens of nucleotide sequences have no common structure other than being nucleic acid sequences. The specific activity of each single stranded antisense oligonucleotide is dependent upon the specific sequence of nucleotides.
Furthermore, the Markush groupings of the SEQ ID NOs listed in claim 23 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: Each of the SEQ ID NOs is different and targets a different region of the PIKFYVE kinase gene. See Table 1 of the present Specification, for example. Each sequence has its own structure based on its sequence, so while they share a common use, the alternatives do not share a common structure.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
When the Markush grouping is for alternatives of chemical compounds, they shall be regarded as being of a similar nature where the following criteria are fulfilled:
(A) All alternatives have a common property or activity; and
(B)(1) A common structure is present, i.e., a significant structural element is shared by all of the alternatives; or
(B)(2) In cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
In paragraph (B)(1), above, the words “significant structural element is shared by all of the alternatives” refer to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. The structural element may be a single component or a combination of individual components linked together.
In paragraph (B)(2), above, the words “recognized class of chemical compounds” mean that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.
In order for the members of the Markush group to belong to “recognized class of chemical compounds” there must be an expectation that the members of the class will behave in the same way in the context of the claimed invention. In other words, each member of the class could be substituted one for the other with the expectation that the same intended result would be achieved. In the instant case, activity of any specific single stranded antisense oligonucleotide is dependent upon the specific sequence of nucleotides. There is no expectation that any one of the nucleotide sequences as claimed can be substituted for any of the other with a completely different sequence with the expectation of the same activity.
Furthermore, the Patent Office does not have the resources to search dozens of sequences in one application and perform the corresponding examination.
See 37 CFR 1.141(a),
The examination guidelines determined that “up to ten sequences” are reasonable depending upon the circumstances. Each of the instant sequences are structurally unique, each comprising a distinct sequence of nucleotides, each having no common structural core. To search for more than ten of the sequences in the same application would present an undue search and corresponding examination burden. See Examination of Patents with Nucleotide Sequences - OG Date: 27 March 2007, wherein the document explains the rescission of the 1996 Notice that allowed up to ten independent and distinct sequences for search and examination in an application.
Allowable Subject Matter
Claim 24 is allowable.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Terra C. Gibbs whose telephone number is 571-272-0758. The Examiner can normally be reached from 8 am - 5 pm M-F.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Ram Shukla can be reached on 571-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TERRA C GIBBS/Primary Examiner, Art Unit 1635
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