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 .
Application Status
Applicant’s remarks, sequence listing, and amendments to the claims and specification filed September 11, 2025 are acknowledged. Claims 1, 4, 10-11, 13, and 19 were amended, and claim 15 was cancelled. Accordingly, claims 1, 4-5, 7, 10-11, 13, 19, and 21 are pending and under examination herein.
Withdrawn Rejections
Applicant’s remarks and amendments to the claims have been thoroughly reviewed. The amendments to claim 4 resolve the Improper Markush Grouping rejection raised in the prior action. The amendments to the claims also resolve the § 112(b) rejections raised in paragraphs 10-11, and 13 of the prior action, and the § 112(d) rejection raised in paragraph 15 of the prior action. The aforementioned rejections are withdrawn, accordingly.
Applicant’s amendments and remarks have been considered, but are not sufficient to place the claims in condition for allowance for the reasons that follow. Any objection or rejection not reiterated herein has been overcome by amendment.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency. As described in the “Sequence Listing Report” dated September 11, 2025, a sequence listing in ST.25 format (i.e., ASCII text format) is required in this application. The sequence listing filed September 11, 2025 was submitted in XML format, which is not permitted in an application having an international filing date before July 1, 2022. See the “Sequence Listing Report” dated September 11, 2025 for further details.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure in ST.25 format; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994). 7.
The disclosure of the prior-filed foreign application, Application No. AU2018903950, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, Application No. AU2018903950, while disclosing instant SEQ ID NOs: 1-32, does not disclose SEQ ID NOs: 33-41. The first disclosure of the SEQ ID NOs: 33-41 is Application No. PCT/AU2019/050996, filed September 18, 2019. Because all claims recite SEQ ID NOs: 33-41, which were first disclosed September 18, 2019, all claims have an effective filing date of September 18, 2019 (i.e., the filing date of Application No. PCT/AU2019/050996).
Claim Objections
Claims 1 and 10 are objected to because of the following informalities:
Claims 1 and 10 recite “PTPN1 pre-mRNA,” and it would be preferable to amend the claims to recite “PTPN1 pre-mRNA” consistent with the term’s notation earlier in the claims, and in the specification.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1, 4-5, 7, 10-11, 13, 19, and 21 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. The rejections that follow are maintained and modified, or new, as necessitated by Applicant’s amendments to the claims.
Claim 1 recites “the antisense oligomer consists of sequences with at least 92% sequence identity to SEQ ID NO: 1, 10, 11, and 31-41.” First, it is not clear whether the phrase “consists of” (I) is intended to require selection of the antisense oligomer from a set of “sequences with at least 92% sequence identity to SEQ ID NO: 1, 10, 11, and 31-41,” or (II) should be interpreted literally, such that the antisense oligomer “consists of” multiple “sequences,” each comprising “at least 92% [] identity” to the recited SEQ ID NOs. It is also not clear how the phrase “92% sequence identity to SEQ ID NO: 1, 10, 11, and 31-41” should be interpreted because each SEQ ID NO sets forth a distinct sequence, and therefore, each SEQ ID NO has various levels of identity to other SEQ ID NOs (see Table 1). Interpreted literally, the phrase appears to require 92% identity to each of the recited SEQ ID NOs, but given the disparate identity levels between the various SEQ ID NOs, it is not clear whether this is a reasonable interpretation of the phrase. It is not clear whether the phrase should instead be interpreted as requiring, for example, 92% identity across a portion of one or more of the recited SEQ ID NOs, or the full length of only one of the recited SEQ ID NOs. Taken together, the structure of the antisense oligomer which “consists of sequences with at least 92% sequence identity to SEQ ID NO: 1, 10, 11, and 31-41” is unclear.
Claims 4-5, 7, 10-11, 13, 19, and 21 are rejected for depending from claim 1 and failing to remedy the indefiniteness.
In the interest of compact prosecution, as it is believed to be one of Applicant’s preferred embodiments based on the specification (see at least [0051]), the aforementioned phrase in claim 1 will be interpreted as requiring an antisense oligomer consisting of a sequence comprising at least 92% sequence identity to one of SEQ ID NOs: 1, 10, 11, and 31-41.
(Maintained and Modified) Claim 7 recites “The antisense oligomer of claim 1 that is:… selected from the list consisting of SEQ ID NO: 1, 32, 33, 34, 35, and 36.” The recited SEQ ID NOs do not have a modified backbone structure based on the sequence listing. Because the claim requires that the “antisense oligomer… is” a recited SEQ ID NO, it is not clear whether option (ii) of claim 7 still requires the second structural element of the antisense oligomer of claim 1, i.e., the “modified backbone structure.”
In the interest of compact prosecution, claim 7 (ii) will be interpreted as requiring an antisense oligomer consisting of a sequence with 100% identity to one of SEQ ID NOs: 1, or 32-36, wherein the antisense oligomer comprises a modified backbone structure.
Response to Remarks - 35 USC § 112(b)
Applicant’s remarks regarding the § 112(b) rejections raised in the prior action have been reviewed. With respect to the rejection of claim 7 which is maintained and modified above, Applicant asserts that the amendments to claim 1 to “remove reference to the nucleobase sequence” remedy the prior rejection. Examiner does not agree that the amendments to claim 1 resolve the rejection of claim 7. Claim 1 requires an antisense oligomer with a modified backbone structure. Claim 7 option (ii) encompasses an antisense oligomer which “is… selected from” a list of SEQ ID NOs, i.e., the antisense oligomer is a sequence as set forth in the sequence listing for one of the recited SEQ ID NOs. None of the recited SEQ ID NOs have a modified backbone structure based on the sequence listing. Thus, it is no longer clear whether the antisense oligomers encompassed by claim 7 option (ii) require the modified backbone structure required of claim 1.
Claim Rejections - 35 USC § 112(d)
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 5 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. The rejection that follows is maintained and modified as necessitated by Applicant’s amendments to the claims.
Claim 5 recites that “if a uracil is present in the antisense oligomer, the uracil (U) of the antisense oligomer is replaced by thymine (T).” This limitation substitutes an antisense oligomer with a “U”-containing sequence, for an antisense oligomer with a “T”-containing sequence, such that the claim no longer requires the nucleobase sequence of the antisense oligomer of claim 1. Therefore, the claim 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.
Response to Remarks - 35 USC § 112(d)
Applicant’s remarks regarding the § 112(d) rejections raised in the prior action have been reviewed. Applicant submits that option (b) of claim 5 “ensures that the oligomer sequences claimed may be either DNA or RNA… [and] ensures that the equivalent DNA sequences of the sequences provided in claim 1 as RNA sequences (e.g., SEQ ID NO: 1, 10, 11, and 31-41) fall within the claim.” First, Examiner notes that no particular nucleotide form is explicitly required of or implied in claim 1. Claim 1 is interpreted herein as requiring an antisense oligomer consisting of a sequence comprising at least 92% sequence identity to one of SEQ ID NOs: 1, 10, 11, and 31-41. Such an antisense oligomer could consist of DNA nucleotides, RNA nucleotides, synthetic nucleotides, or mixtures thereof, and still comprise “at least 92% sequence identity” to a recited SEQ ID NO. Applicant’s assertion that the SEQ ID NOs correspond to RNA sequences is also not supported by the sequence listing, wherein each SEQ ID NO is provided as “DNA.” Finally, Applicant’s assertion that claim 5 option (b) is intended to encompass the “equivalent DNA sequences,” also does not remedy the rejection given that I) such forms are already encompassed by instant claim 1, and II) the SEQ ID NOs are already set forth as “DNA” sequences in the sequence listing. Applicant’s remarks do not resolve the fact that claim 7 option (b) substitutes a “U”-containing antisense oligomer of claim 1, for a distinct, “T”-containing antisense oligomer, and that accordingly, all the limitations of claim 1 are not required of claim 7 option (b).
Claim Rejections - 35 USC § 112(a) – Written Description
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, 4-5, 7, 10-11, 13, 19, and 21 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 rejection is maintained with modification necessitated by Applicant’s amendments.
MPEP 2163.II.A3.(a).(i) states the following:
“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 inventor was in possession of the claimed genus.”
“Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
Species Encompassed
In view of the indefiniteness described above, claim 1 is interpreted as requiring an antisense oligomer consisting of a sequence with at least 92% identity to one of the recited SEQ ID NOs, wherein the oligomer has a modified backbone structure. SEQ ID NOs: 1, 10, 11, and 31-36 are 25mers or 23mers (i.e., SEQ ID NO: 31) with 100% identity to the human PTPN1 gene, and therefore, 100% complementarity to the pre-mRNA transcribed therefrom (see alignment of record between SEQ ID NO: 1-36 and NG_012119.2). SEQ ID NOs: 37-41 are 25mers 100% complementary across their full length (SEQ ID NOs: 37-38, 41) or across 22/25 nucleobases (SEQ ID NO: 39), or with a single mismatch (SEQ ID NO: 40) to a mouse PTPN1 transcript (see attached alignment between SEQ ID NOs: 37-41 and Mus musculus Reference RNA sequences (refseq_rna)). A “modified backbone structure” is interpreted as a backbone having at least one linkage that is not the standard phosphodiester linkage found in naturally-occurring oligomers and polynucleotides, e.g., a backbone having at least one phosphorothioate linkage ([0073]-[0074]). Accordingly, the claim encompasses antisense oligomers consisting of a sequence comprising no more than a) one mismatched nucleobase relative to SEQ ID NO: 31 (22/23 = 95.6% identity), or b) two mismatched nucleobases relative to SEQ ID NOs: 1, 10-11, and 32-41 (23/25 = 92% identity), and at least one non-naturally occurring linkage.
Central to the rejection herein, the genus is not limited to an antisense oligomer consisting of one of the recited SEQ ID NOs, or an antisense oligomer 23nts or 25nts in length comprising at least 92% identity to one of the recited SEQ ID NOs. The genus encompasses many, diverse sequences, of essentially any length, provided the sequence comprises at least 92% identity to a recited SEQ ID NO. The claimed antisense oligomer must “induce[] alternative splicing of PTPN1 pre-mRNA through exon 2 skipping,” and “inhibit[] the expression of PTP1B,” i.e., the protein encoded by PTPN1 ([0023]-[0024]). The phrase “inhibit the expression of PTP1B” is interpreted as encompassing any mode of inhibition, e.g., reducing the amount of PTPN1 RNA ([0029]), reducing the amount of PTP1B (Fig. 16B), and/or reducing the amount of functional PTP1B, e.g., by interfering with splicing ([0030]). For the reasons that follow, the specification has not adequately described the genus of antisense oligomers encompassed by the claim which achieve the required functional limitations.
Species Disclosed in the Specification
The specification describes 41 antisense oligomers targeted to PTPN1 pre-mRNA, each consisting of a sequence 100% identical to one of SEQ ID NOs: 1-41 (Table 1; [00188], “General methods”). The specification describes two chemistries for the aforementioned antisense oligomers – a phosphorothioated (PS) 2’-O-methyl (2’OMe) form ([00188]), and a phosphorodiamidate morpholino oligomer (PMO) form ([00194]). The specification also describes an antisense oligomer (“ISIS 107773”) which consists of nucleotides 6-25 of SEQ ID NO: 1 in a 5-10-5 2’-O-methoxyethyl (MOE) gapmer form, or a phosphorothioated (PS) 2’-O-methyl (2’OMe) form ([00190]). ISIS 107773 has 80% identity to SEQ ID NO: 1 (see alignment of record).
The specification demonstrates that antisense oligomers consisting of one of SEQ ID NOs: 1-4, 10-15, 18-19, 23-25, 27, 29, and 31-41 in a phosphorothioated (PS) 2’-O-methyl (2’OMe) form induce exon 2 skipping of PTPN1 pre-mRNA, thereby decreasing the amount of the full-length PTPN1 transcript (Figs. 2-4, 8, 12, 17; Table 2, “Full length knockdown efficiency”). The specification also shows that an antisense oligomer consisting of SEQ ID NO: 33, in either the phosphorothioated (PS) 2’-O-methyl (2’OMe) or PMO form, induces exon 2 skipping of PTPN1 pre-mRNA, decreases the amount of full-length PTPN1 transcript, and reduces the amount of PTP1B protein (Figs. 15-16). The specification demonstrates that both the gapmer form and PMO form of ISIS 107773 (consisting of nts 6-25 of SEQ ID NO: 1) induce exon 2 skipping of PTPN1 pre-mRNA, thereby decreasing the amount of the full-length PTPN1 transcript (Fig. 10, 13; Table 2, “Full length knockdown efficiency”).
Taken together, the specification demonstrates that antisense oligomers consisting of SEQ ID NOs: 1, 10-11, 31-41, and ISIS 107773, with specific chemistries, induce exon 2 skipping of PTPN1 pre-mRNA and reduce the amount of full-length PTPN1 transcript (i.e., “inhibit the expression of PTP1B”). The specification does not describe any other antisense oligomers encompassed by the claimed genus which induce exon 2 skipping or alternative splicing of PTPN1 pre-mRNA, or which “inhibit expression of PTP1B.” For example, with the exception of ISIS 107773, the specification does not describe any antisense oligomers which have less than 100% identity to a recited SEQ ID NO, which are longer or shorter than a recited SEQ ID NO, or which have any alternative chemistries to those described immediately above. The specification also fails to provide predictability that such antisense oligomers would be capable of fulfilling the recited functions. For example, the specification demonstrates that only a subset of the antisense oligomers designed to target PTPN1 pre-mRNA actually induce exon 2 skipping (see at least Figs. 2-4, lanes 5-9, 16-17, 20-22, 26, 28, 30, corresponding to the respective “AO”). As shown in Table 1, even antisense oligomers targeting regions in close proximity to one another fail to produce similar levels of exon 2 skipping (e.g., “PTPN1 1E9A (+67+92)” corresponding to lane 28 vs. “PTPN1 1E9A (+98+123)” corresponding to lane 29; Fig. 4). See alignment of record. The specification, while acknowledging that only a subset of the antisense oligomers are effective ([00188]), fails to provide sufficient guidance for the skilled artisan to reasonably predict the structures of antisense oligomers which would induce exon 2 skipping.
Guidance in the Art
The prior art was searched for additional species within the claimed genus. The search uncovered antisense oligomers targeted to PTPN1 pre-mRNA, e.g., Bhanot which describes ISIS 107773 (summarized in paragraph 15 of the action dated October 22, 2024). The search did not uncover any antisense oligomers encompassed by claim 1 that were explicitly disclosed as PTPN1 pre-mRNA splicing modulators before the effective filing date. The art was also searched for guidance in designing antisense oligomers which inhibit the expression of a target mRNA by interfering with splicing.
Aartsma-Rus (Aartsma-Rus, 2012, Exon Skipping: Methods and Protocols, Methods in Molecular Biology, 867, Chapter 8, pg. 117-129; of record) teaches “generalizable” guidelines to design antisense oligomers that interfere with splicing, i.e., guidelines which Aartsma-Rus teaches apply to multiple gene targets (pg. 118). Aartsma-Rus teaches that the antisense oligomer’s chemistry must promote stability of the oligomer and affinity for the target RNA (pg. 118). Aartsma-Rus teaches that phosphorothioated (PS) 2’-O-methyl (2’OMe) (“2OMePS”) and PMO forms – the most commonly used chemistries – offer oligomer stability, affinity for the target RNA, and prevent RNase H cleavage, the latter of which is ideal for modulating splicing because it prevents cleavage of the hybridized duplex (pg. 118). Furthermore, Aartsma-Rus teaches that the optimal length for most 2OMePS antisense oligomers is 20nts, although some may be longer (between 25-30nts). Aartsma-Rus teaches that antisense oligomers with GC percentages greater than 40% and/or with higher Tm (over 48°C) are most effective, although at GC percentages greater than 60%, the tendency for self-hybridization decreases efficiency (pg. 119-120; Table 1).
In addition to having sufficient affinity to the target, Aartsma-Rus teaches that the antisense oligomer must be designed to bind at an accessible target site (pg. 121). Aartsma-Rus teaches that pre-mRNAs form dynamic secondary structures (pg. 121), and that effective antisense oligomers likely severely disrupt the pre-mRNA secondary structure (pg. 123). Such folding can be estimated using available software (e.g., “m-fold software”) (pg. 122-123). Aartsma-Rus teaches that effective target sites for splice-modulating antisense oligomers include 3’, 5’, and exon-internal sequences, the latter of which outperform splice sites owing to their improved thermodynamic properties (pg. 123). Regarding exon-internal target sites, Aartsma-Rus teaches that the most effective target sites were located closer to 3’ splice sites and targeted exonic splicing enhancer (ESE) sites (pg. 123-124). Finally, Aartsma-Rus provides a method to design exon-internal 2OMePS antisense oligomers with “~80% success for exons of various genes targeted so far” (pg. 124-126). The method utilizes antisense oligomers that are 100% complementary to their target sequence (pg. 125, Fig. 4).
While Aartsma-Rus provides guidance as to the general factors influencing splice modulation by antisense oligomers, and a method to design splice modulating oligomers, Aartsma-Rus also strongly suggests that there is a level of unpredictability in producing an effective splice-modulating antisense oligomer, describing the process as involving “trial and error” (“there are also effective AONs that do not fulfill these criteria and similarly there are AONs that fulfill all criteria and are ineffective”, pg. 126; “there is also a trial and error aspect involved. Generally, at least one AON is effective when two AONs are tested for a single exon”, pg. 127).
Taken together, the prior art suggests that antisense oligomers targeting PTPN1 pre-mRNA may interfere with splicing, but a search did not uncover any examples of known PTPN1 pre-mRNA splice-modulating antisense oligomers before the effective filing date. The prior art teaches guidelines to design oligomers to interfere with pre-mRNA splicing – e.g., chemistries which promote oligomer stability, increase target affinity, and prevent RNase H cleavage, as well as preferred target site locations based on thermodynamic properties, locations of splice sites and ESE sites, etc. However, the prior art also strongly suggests that design principles, even when strictly applied, may generate antisense oligomers which are incapable of modulating PTPN1 pre-mRNA splicing. This teaching is supported by the specification, wherein only a portion of the antisense oligomers 100% complementary to their target sequence, and comprising one of Aartsma-Rus’s preferred chemistries, induce exon 2 skipping of PTPN1 pre-mRNA (see at least Figs. 2-4, lanes 5-9, 16-17, 20-22, 26, 28, 30, corresponding to the respective “AO”).
Conclusion
The specification describes antisense oligomers that fulfill the claimed functions, and which consist of one of the recited SEQ ID NOs, in one of two specific chemical modification patterns, i.e., antisense oligomers consisting of one of SEQ ID NOs: 1, 10, 11, and 31-41 in a phosphorothioated (PS) 2’-O-methyl (2’OMe) form ([00188]-[00190]), and an antisense oligomer consisting of SEQ ID NO: 33 in a PMO form ([00194]-[00195]). This is a small fraction of the antisense oligomers encompassed by the claimed genus.
The specification also provides exemplary antisense oligomers which meet splice-modulating antisense oligomer criteria described by the prior art, but fail to actually induce exon 2 skipping of PTPN1 pre-mRNA. Indeed, the prior art strongly suggests that the claimed characteristics alone are not predictive of the efficacy of an antisense oligomer because factors including the length, Tm, GC content, self-hybridization, and target site affinity impact splice modulation abilities. These factors would be impacted at least by the presence of I) any number of and sequence of nucleotides surrounding the sequence with at least 92% identity to one of the recited SEQ ID NOs, II) substitutions of up to two nucleotides relative to one of the recited SEQ ID NOs, and III) the oligomer’s chemical modification pattern. Neither the specification nor art as of the effective filing date, provide a reasonable structure-function relationship that would allow the skilled artisan to predict which of the many antisense oligomers in the genus would induce exon 2 skipping and inhibit PTP1B expression as claimed.
Thus, considering the large variation in the genus, the small percentage of species described in the specification and art, and the lack of a reasonable structure-function relationship provided by the specification or art for the full scope of the claimed genus, it is reasonable to conclude that Applicant did not possess the invention as claimed at the time of filing.
Dependent Claims
Claims 4-5, 7, 10-11, 13, 19, and 21 do not further limit the genus of antisense oligomers so as to resolve the issues above, and are therefore not sufficiently described for the reasons above.
Response to Remarks - Written Description
Applicant’s remarks regarding the written description rejection raised in the prior action have been thoroughly reviewed. Applicant submits that the rejection is overcome by amendments to claim 1 which allegedly narrow the scope of antisense oligomers to a “very limited and defined set of sequences and one that is easily tested by a person of skill in the art.” Applicant alleges that the claimed set of sequences “only differ[s] from those tested by one or two bases,” and that the skilled artisan would predict that “very slightly different sequences would also work.”
Again, Examiner respectfully disagrees with Applicant’s characterization of the scope of antisense oligomers encompassed by the claims. Claim 1 is interpreted herein as encompassing antisense oligomers which consist of “sequences with at least 92% sequence identity” to one of the recited SEQ ID NOs. The sequence may be of any length so long as it comprises at least 92% sequence identity to one of the recited SEQ ID NOs. Thus, contrary to Applicant’s assertions, the amendments have not narrowed the scope of antisense oligomers to a “very limited and defined set of sequences,” or those which only differ “very slightly” from the exemplary antisense oligomers, e.g., by “one or two bases.” The sequences encompassed may have any number of and sequence of nucleotides outside of the portion with at least 92% identity to a recited SEQ ID NO. As described in each of the prior rejections and above, and as conceded by Applicant “The nature of antisense oligomers is that the level of activity of different sequences is inherently unpredictable if they differ significantly.” The genus of antisense oligomers currently encompassed by the claims “differ[s] significantly” from the functional antisense oligomers described in the specification, i.e., oligomers consisting of one of the recited SEQ ID NOs in a specific chemical form, i.e., either a phosphorothioated (PS) 2’-O-methyl (2’OMe) or PMO form.
Applicant also appears to assert that the exemplary antisense oligomers corresponding to SEQ ID NOs: 28 and 29 do not illustrate unpredictability for the claimed antisense oligomers. Applicant also asserts that “sequences with 92% identity to SEQ ID NO: 1, 10, 11, and 31-41 would be likely to have similar (if not identical) levels of activity.” First, the unpredictability for the claimed genus was not established based on a comparison of a single pair of exemplary antisense oligomers characterized in the specification. The unpredictability was established based on the guidance in the specification and prior art relative to the scope of the claims. Applicant’s remarks specific to two exemplary antisense oligomers does not address the lack of predictability related to the failure of the specification or prior art to sufficiently describe antisense oligomers with the claimed function that (I) have less than 100% identity to a recited SEQ ID NO, (II) are longer or shorter than a recited SEQ ID NO, and/or (III) have any chemistry. The prior art suggests that design principles, even when strictly applied, will generate antisense oligomers which are incapable of modulating PTPN1 pre-mRNA splicing. Indeed, Aartsma-Rus describes the design of splice skipping antisense oligomers as involving “trial and error.” This teaching is supported by the specification, wherein only a portion of the antisense oligomers 100% complementary to their target sequence, and comprising one of Aartsma-Rus’s preferred chemistries for splice skipping, induce exon 2 skipping of PTPN1 pre-mRNA (see at least Figs. 2-4, lanes 5-9, 16-17, 20-22, 26, 28, 30, corresponding to the respective “AO”). None of Applicant’s remarks, the specification, or prior art teach or suggest that “sequences with 92% identity to SEQ ID NO: 1, 10, 11, and 31-41 would be likely to have similar (if not identical) levels of activity” as Applicant asserts. Varying the sequence would likely change the affinity of an exemplary antisense oligomer for its target sequence, in an unpredictable manner, such that based on the prior art, the activity of the variant oligomer would also not be predictable.
Finally, Applicant alleges that “while some chemistries may promote more stability than others, the basic chemistry does not change whether a given antisense oligomer sequence works or not.” In support of this argument, Applicant cites that “changing the chemistry of SEQ ID NO: 33 from 2’OMe to PMO did not render it nonfunctional, nor did changing the chemistry of non-claimed prior art sequence ISIS 107773 from gapmer to PMO.” Examiner respectfully disagrees with Applicant’s conclusions. First, as stated in the prior action and above, SEQ ID NO: 33 was changed from one prior art recognized chemistry for splice skipping (phosphorothioated (PS) 2’-O-methyl (2’OMe)), to another prior art recognized chemistry for splice skipping (PMO). Examiner has already indicated that the skilled artisan would expect both of these prior art chemistries to be effective to promote splice skipping.
Aartsma-Rus teaches that the antisense oligomer’s chemistry must promote stability of the oligomer and affinity for the target RNA (pg. 118). Aartsma-Rus teaches that phosphorothioated (PS) 2’-O-methyl (2’OMe) (“2OMePS”) and PMO forms – the most commonly used chemistries – offer oligomer stability, affinity for the target RNA, and prevent RNase H cleavage, the latter of which is ideal for modulating splicing because it prevents cleavage of the hybridized duplex (pg. 118). Aartsma-Rus’ teachings are supported by Havens (Havens and Hastings, 10 June 2016, Nucleic Acids Research, Vol. 44, Issue 14, pg. 6549-6563), which is cited herein solely to respond to Applicant’s arguments. Havens states that “nucleotides of an SSO are chemically modified so that the RNA-cleaving enzyme RNase H is not recruited to degrade the pre-mRNA-SSO complex… The RNase H-resistant features of SSOs are critical because the goal of SSOs is to alter splicing and not to cause the degradation of the bound pre-mRNA” (pg. 6550-6551).
A gapmer form, such as that of ISIS 107773, permits RNase H cleavage. Based on the prior art cited above, this chemistry would not be predicted to be effective for splice skipping; although, Examiner also notes Aartsma-Rus’ assertions of unpredictability and “trial and error” (pg. 126-127), which suggest that non-preferred chemistries may be effective in certain contexts, although such contexts are unpredictable. Examiner acknowledges that ISIS 107773 in gapmer form does appear to promote splice skipping (Fig. 10, “ISIS 107773 MOE gapmer”); however, Applicant’s data also demonstrates that modifying the chemistry of ISIS 107773 to a prior art recognized chemistry for splice skipping improves its efficacy (Fig. 10, “ISIS 107773 2-OMePS”). Applicant does not test any other antisense oligomers in gapmer form, so as to rebut the apparent consensus in the art that RNase H-resistant chemistries are “critical” for splice skipping antisense oligomers. In addition, there are examples in the art which illustrate that gapmer forms of antisense oligomers are not functional for splice skipping. See Figs. 5-6 of Ward (Ward et al., Nucleic Acids Research, 3 March 2014, Vol. 42, Issue 9, pg. 5871-5879). Given the guidance in the prior art regarding the criticality of RNase H-resistant chemistry for splice skipping oligomers, the unpredictability for non-preferred chemistries (and, even for preferred chemistries), and the prior art gapmer forms that are not functional for splice skipping, it is not predictable that chemistries other than those described by Applicant and accepted by the prior art, i.e., phosphorothioated (PS) 2’-O-methyl (2’OMe) (“2OMePS”) and PMO forms, would be functional.
Taken together, Applicant’s remarks do not address the lack of sufficient guidance for the skilled artisan to predict which antisense oligomers encompassed by the claim will actually meet the claimed functional limitations. The rejection is maintained and modified, accordingly.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
Method of Inducing Alternative Splicing
Claim 10 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The specification is enabling for a method of inducing alternative splicing of PTPN1 pre-mRNA by providing one or more antisense oligomers consisting of SEQ ID NOs: 1, 10, 11 and 31-41 in a PMO or phosphorothioated (PS) 2’-O-methyl (2’OMe) form, or an antisense oligomer consisting of nts 6-25 of SEQ ID NO: 1 in a 5-10-5 MOE gapmer form, and allowing the oligomer(s) to bind to a target nucleic acid site. The specification does not reasonably provide enablement for a method of inducing alternative splicing of PTPN1 pre-mRNA by providing one or more antisense oligomers of claim 1. 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 for the reasons that follow. The following rejection is maintained with modification necessitated by Applicant’s amendments.
The test of enablement is whether one skilled in the art could make or use the claimed invention from the disclosures in the specification coupled with information known in the art without undue experimentation (United States v. Telectronics Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988)). Whether undue experimentation is needed is not based upon a single factor, but rather is a conclusion reached by weighing many factors. These factors were outlined in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), and the most relevant factors are indicated below:
Nature of the Invention and Breadth of Claim
Claim 10 recites “A method for inducing alternative splicing of PTPN1 pre-mRNA.” The method requires “providing one or more antisense oligomers according to claim 1, and allowing the oligomer(s) to bind to a target nucleic acid site.” The claim also repeats the functional language from claim 1 (“wherein the antisense oligomer induces…”). A detailed description of the antisense oligomers encompassed by claim 1 is described in paragraph 16 above and applied hereinafter. Enablement of the claim requires that one of ordinary skill in the art be able to induce alternative splicing of PTPN1 pre-mRNA by providing one or more of the antisense oligomers described in paragraph 16 above, and allowing the oligomer(s) to bind to a target site.
Guidance in the Specification
The guidance in the specification is described above in paragraph 17 and applied hereinafter. Briefly, the specification demonstrates that antisense oligomers consisting of one of SEQ ID NOs: 1-4, 10-15, 18-19, 23-25, 27, 29, and 31-41 in a phosphorothioated (PS) 2’-O-methyl (2’OMe) form induce alternative splicing of PTPN1 pre-mRNA (i.e., exon 2 skipping of PTPN1 pre-mRNA) (Figs. 2-4, 8, 12, 17; Table 2). The specification also shows that an antisense oligomer consisting of SEQ ID NO: 33 in a PMO form induces alternative splicing of PTPN1 pre-mRNA (Figs. 15-16). The specification demonstrates that both the gapmer form and PMO form of ISIS 107773 (consisting of nts 6-25 of SEQ ID NO: 1) induce alternative splicing of PTPN1 pre-mRNA (Fig. 10, 13; Table 2).
Taken together, the specification demonstrates that antisense oligomers consisting of SEQ ID NO: 1-4, 10-15, 18-19, 23-25, 27, 29, and 31-41, and ISIS 107773, in specific chemically modified forms induce alternative splicing of PTPN1 pre-mRNA. The specification does not describe any other antisense oligomers encompassed by the claimed genus which induce exon 2 skipping or alternative splicing of PTPN1 pre-mRNA. For example, with the exception of ISIS 107773, the specification does not describe any antisense oligomers which have less than 100% identity to a recited SEQ ID NO, which are longer or shorter than a recited SEQ ID NO, or which have any alternative chemistries to those described immediately above. The specification also fails to provide predictability that such antisense oligomers would be capable of fulfilling the recited functions. For example, the specification demonstrates that only a subset of the antisense oligomers designed to target PTPN1 pre-mRNA actually induce exon 2 skipping (see at least Figs. 2-4, lanes 5-9, 16-17, 20-22, 26, 28, 30, corresponding to the respective “AO”). As shown in Table 1, even antisense oligomers targeting regions in close proximity to one another fail to produce similar levels of exon 2 skipping (e.g., “PTPN1 1E9A (+67+92)” corresponding to lane 28 vs. “PTPN1 1E9A (+98+123)” corresponding to lane 29; Fig. 4). See attached alignment. The specification, while acknowledging that only a subset of the antisense oligomers are effective ([00188]), fails to provide sufficient guidance for the skilled artisan to reasonably predict which structures of antisense oligomers would induce exon 2 skipping.
State of the Art
As described in paragraph 18 above, a thorough search of the art uncovered antisense oligomers targeted to PTPN1 pre-mRNA (e.g., Bhanot, ISIS 107773); however, the search did not uncover any antisense oligomers encompassed by claim 1 that were explicitly disclosed as PTPN1 pre-mRNA splicing modulators before the effective filing date. Accordingly, the art was also searched for guidance in designing antisense oligomers which inhibit the expression of a target mRNA by interfering with splicing. The teachings of Aartsma-Rus are described above in paragraph 18 and applied hereinafter.
Briefly, Aartsma-Rus teaches guidelines and a method to design oligomers to interfere with pre-mRNA splicing – e.g., chemistries which promote oligomer stability, increase target affinity, and prevent RNase H cleavage, as well as preferred target site locations based on thermodynamic properties, locations of splice sites and ESE sites, etc. However, Aartsma-Rus also strongly suggests that there is a level of unpredictability in producing an effective splice-modulating antisense oligomer, describing the process as involving “trial and error” (“there are also effective AONs that do not fulfill these criteria and similarly there are AONs that fulfill all criteria and are ineffective”, pg. 126; “there is also a trial and error aspect involved. Generally, at least one AON is effective when two AONs are tested for a single exon”, pg. 127). This teaching is supported by the specification, wherein only a portion of the antisense oligomers 100% complementary to their target sequence, and comprising one of Aartsma-Rus’s preferred chemistries, induce exon 2 skipping of PTPN1 pre-mRNA (see at least Figs. 2-4, lanes 5-9, 16-17, 20-22, 26, 28, 30, corresponding to the respective “AO”).
Experimentation Required and Level of Skill in the Art
In order to practice the invention, a large amount of highly unpredictable experimentation would be required. For example, one of ordinary skill would need to design and synthesize antisense oligomers commensurate with the scope of claim 1. The skilled artisan would then need to determine whether the antisense oligomers induce alternative splicing of PTPN1 pre-mRNA, e.g., by using the assays described in the specification (Examples 1-4). This experimentation is within the capabilities of one of ordinary skill in the art, as evidenced by the instant specification and prior art. However, such experimentation is undue because of I) the number of distinct species encompassed by claim 1, including many which fall outside of the optimal design principles for splice-modulating antisense oligomers, and II) the strong suggestion in the prior art that even when such optimal design principles are strictly applied, a portion of the resulting antisense oligomers may be incapable of modulating splicing. The prior art uses the phrase “trial and error” to describe the design of antisense oligomers that induce alternative splicing. Indeed, as evidenced by the specification, only a portion of the antisense oligomers 100% complementary to their target sequence, and comprising one of Aartsma-Rus’s preferred chemistries, induce exon 2 skipping of PTPN1 pre-mRNA (see at least Figs. 2-4, lanes 5-9, 16-17, 20-22, 26, 28, 30, corresponding to the respective “AO”).
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claim, the guidance provided in the specification and art, the lack of working examples to meet the scope of the claim, and the lack of predictability provided by the specification or art for the genus of antisense oligomers encompassed by the method, it is the conclusion that undue experimentation would be required to use the invention as claimed.
Response to Remarks - Method of Inducing Alternative Splicing
Applicant’s remarks regarding the scope of enablement rejection over claim 10 have been reviewed. Applicant points to the amendments to the claims and the remarks directed to the written description rejection as resolving the rejection. Examiner has considered the scope of the amended claims, the examples in the specification, as well as the teachings of the prior art. The claims are not limited to the functional antisense oligomers exemplified in the specification, and the specification and prior art fail to provide sufficient guidance for the skilled artisan to predict which of the antisense oligomers encompassed by claim 1 would actually function in a method of inducing alternative splicing of PTPN1 pre-mRNA. The rejection is maintained and modified, accordingly.
Method of Treating, Preventing, or Ameliorating the Effects of a Disease Associated with PTP1B
Claim 13 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The specification is enabling for a method of treating or ameliorating the effects of type 2 diabetes and/or obesity, and certain solid cancers with an antisense oligomer that inhibits PTP1B by decreasing the overall amount of PTPN1 mRNA or PTP1B protein (see Cruz, below). The specification does not reasonably provide enablement for a method of treating or ameliorating the effects of type 2 diabetes, obesity, or the specifically recited solid cancers with an antisense oligomer that induces exon 2 skipping of PTPN1 pre-mRNA. 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 for the reasons that follow. The following rejection is maintained with modification necessitated by Applicant’s amendments.
Nature of the Invention and Breadth of Claims
Claim 13 recites a method of treating or ameliorating the effects of a disease associated with PTP1B, wherein the disease is type 2 diabetes, obesity, or a specific solid cancer, wherein the method comprises administering to a subject an effective amount of one or more antisense oligomers according to claim 1, or a pharmaceutical composition comprising one or more antisense oligomers according to claim 1. A detailed description of the antisense oligomers encompassed by claim 1 is described in paragraph 16 above and applied hereinafter. Enablement of the claim requires that one of ordinary skill in the art be able to treat or ameliorate the effects of type 2 diabetes, obesity, or a specific solid cancer, by administering an effective amount of one or more antisense oligomers encompassed by claim 1, or a pharmaceutical composition comprising the same.
Guidance in the Specification
The specification demonstrates that PTP1B is expressed in various cancer cell types (Example 5, Fig. 20). The specification teaches that PTP1B is a therapeutic target for both type 2 diabetes and obesity, owing to the fact that its expression negatively regulates insulin and leptin signaling pathways ([0005]). The specification also teaches that PTP1B plays a role as an oncogene ([0007]). The specification does not demonstrate treatment or amelioration of the effects of any disease by administering any antisense oligomer encompassed by claim 1. The specification does demonstrate that antisense oligomers consisting of one of SEQ ID NOs: 1, and 32-36 in 2’OMePS form, induce exon 2 skipping of PTPN1, and reduce full-length PTPN1 transcript levels in Huh-7, HepG2, and IHH cells (Table 2, pg. 46).
State of the Art
The art was searched for examples of and guidance in treating or ameliorating the effects of diseases associated with PTP1B by inhibiting PTPN1 mRNA or PTP1B expression generally, or by interfering with PTPN1 pre-mRNA splicing.
Cruz (Cruz et al., 2021, Bioscience Reports, (2021) 41, BSR20211994, p. 1-12, of record) provides a review of the role of PTP1B in metabolism and cancer. Cruz teaches that PTP1B plays a prominent role in insulin and leptin signaling (pg. 4). Regarding insulin signaling, Cruz teaches that knocking out PTP1B in mice improves glucose homeostasis and insulin signaling in muscle and liver, and that neuronal-specific PTP1B knock out prevents diet-induced obesity and glucose intolerance (pg. 4). Regarding leptin signaling, Cruz teaches that neuronal-specific PTP1B knockout in mice promotes thin-ness even in the presence of a hypercaloric diet, and improves leptin sensitivity and energy expenditure (pg. 4). Cruz does not provide guidance on the role of PTP1B truncation or splice variants in type 2 diabetes or obesity.
Regarding the role of PTP1B splice variants in type 2 diabetes, Bhanot teaches that PTP1B is expressed in insulin sensitive tissues as two different isoforms resulting from alternative splicing of pre-mRNA (col. 2, lines 13-17). Bhanot teaches that the levels of the two alternatively spliced isoforms correlate with plasma insulin concentration and percentage body fat, and thus, they may be correlated with chronic hyperinsulinemia and/or type 2 diabetes (col. 2, lines 21-25). Indeed, Ugi (Ugi et al., 2009, J. Biochem. 146(4), p. 541-547, of record) teaches that hepatic overexpression of wildtype PTP1B, or a C-terminal truncated PTP1B (“PTP1B∆CT”) promotes elevated fasting plasma glucose levels (i.e., fasting hyperglycemia), and insulin resistance in mice (pg. 543; Fig. 2). The C-terminal truncated PTP1B did not lead to hypertriglyceridemia, however (Fig. 2C). Ugi concludes that the in vivo studies demonstrate a role for PTP1B in promoting insulin resistance and hypertriglyceridemia, the latter of which requires that PTP1B have the C-terminal region (pg. 546). Ugi’s findings are relevant because the instant specification states that exon 2 skipping by the instant antisense oligomers seeks to “increase the production of truncated, nonsense or prematurely terminated proteins,” ([0029]) e.g., “preferably, the present invention leads to skipping of exon 2, to induce pre-mature stop codons in exon 3 ([0033]). Based on Ugi, the skilled artisan would reasonably conclude that increasing the levels of C-terminal truncated PTP1B in the liver (e.g., with antisense oligomers that promote such truncation) may actually increase fasting hyperglycemia and insulin resistance associated with diabetes. The search did not uncover any additional studies which examined the role of specific PTP1B splice variants in type 2 diabetes or obesity.
Regarding cancers, Cruz teaches that PTP1B serves as both a tumor promoter and tumor suppressor depending on the cellular context (pg. 5). For example, Cruz teaches that PTP1B acts as an oncogene in a mouse models of HER2-driven breast cancer (“Neu-driven breast cancer”) (pg. 5). PTP1B is also overexpressed in melanoma, non-small cell lung cancer, and pancreatic ductal adenocarcinoma, where its expression is associated with metastasis and/or tumor stage (pg. 6). Conversely, Cruz teaches that PTP1B acts as a tumor suppressor in some other tumors, e.g., esophageal cancer, lymphoma, glioblastomas (pg. 6). Cruz also teaches that PTP1B splice mutations are found in approximately 20% of human colon and thyroid tumors (pg. 6). Importantly, Cruz teaches that the expression of one truncated splice variant (“PTP1B∆E6” which lacks exon 6) induces oncogenic transformation (pg. 6).
Regarding the role of PTP1B splice variants in cancer, Mei (Mei et al., 17 November 2016, PLOS One, 11(11), p. 1-15, of record) sequenced 43 human colon tumors, and 47 human thyroid tumors and found incorrectly spliced forms of PTP1B, including mutants that lack the entirety of exon 2 (∆E2), 5 (∆E5) or 6 (∆E6), or portions of exon 6 and 7 (∆E6p, ∆E6p/E7p) (pg. 2; Table 1; Fig. 1). These mutants are relevant because the instant specification states that exon 2 skipping by the instant antisense oligomers may remove these exons ([0029]). Mei teaches that PTP1B mutants lacking exon 6 (∆E6) do not have enzymatic activity, whereas those lacking exon 5 (∆E5) have similar phosphatase activity to wildtype PTP1B (pg. 6; Fig. 3). Mei investigated the ability of exon 6 (∆E6) and exon 5 (∆E5) mutants to induce oncogenic transformation in culture, and tumors in vivo (pg. 7; Fig. 4; Table 3). Mei found that cells expressing the PTP1B mutant lacking exon 6 (∆E6) and as a result, phosphatase activity, undergo oncogenic transformation in culture and promote the growth of rapidly growing tumors in vivo (Fig. 4; Table 3).
Mei did not investigate the role of the remaining truncated PTP1B variants, e.g., mutants lacking the entirety of exon 2 (∆E2). However, Zahn (Zahn et al., 2021, Carcinogenesis, 42(4), p. 517-527, of record) characterized an additional PTP1B splice mutant lacking exons 2-4 (∆E2-4). Zahn demonstrates that both the PTP1B splice mutant lacking exon 6 (∆E6), and the PTP1B splice mutant lacking exons 2-4 (∆E2-4) are catalytically inactive (pg. 520; Fig. 2C). Zahn teaches that both mutants, ∆E6 and ∆E2-4, are positive regulators of JAK/STAT activity (pg. 521; Fig. 3-4), and consequently, they increase ectopic cell proliferation when expressed in a Hodgkin’s disease-derived cell line (“L-428”) (Fig. 4C-D). Zahn demonstrates that expression of ∆E6 and ∆E2-4 also promote cellular resistance to chemotherapeutic agents (pg. 522; Fig. 5). Taken together, Zahn demonstrates that a PTP1B mutant lacking exon 6 (∆E6) and a PTP1B splice mutant lacking exons 2-4 (∆E2-4) have a pro-proliferative effect (likely by promoting activation of JAK/STAT signaling), and protective effect against chemotherapeutic agents in a Hodgkin’s lymphoma cell line.
Experimentation Required and Level of Skill in the Art
To practice the invention, a large amount of highly unpredictable experimentation would be required. One of ordinary skill would need to design and synthesize antisense oligomers commensurate with the scope of claim 1. The skilled artisan would then need to select cohorts of subjects having diseases commensurate with the scope of the claims, i.e., type 2 diabetes, the specifically recited solid cancers, and obesity. The skilled artisan would need to design the administration protocols for each cohort of subjects, which would certainly vary depending on the specific disease to be treated, and the efficacy of the specific antisense oligomer(s) delivered. Finally, the skilled artisan would need to administer the antisense oligomer(s), and determine whether any effects of the subject’s diseases were treated, prevented, or ameliorated.
The level of skill in the art is high, and such experimentation is certainly within the capabilities of one of ordinary skill in the art. However, such experimentation is undue because of I) the number of antisense oligomers and antisense oligomer combinations (i.e., “administering… one or more antisense oligomers”) encompassed by the claim, combined with the lack of predictability for the genus of antisense oligomers described in the preceding rejections, II) the absence of working examples in the specification or prior art, III) the strong suggestion in the prior art that inhibiting PTPN1 pre-mRNA generally (i.e., by decreasing the amount of PTPN1 mRNA and/or PTP1B protein), or inducing truncated splice variants of PTP1B, may actually promote certain cancers, e.g., the cancers described in Cruz for which PTP1B acts as a tumor suppressor, and the cancers described in Mei and Zhan, and IV) the lack of evidence in the prior art that inducing truncated splice variants of PTP1B will treat or ameliorate the effects of type 2 diabetes or obesity, and Ugi’s evidence that suggests increasing C-terminal truncated forms of PTP1B may actually promote features of metabolic disease.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claims, the guidance provided in the specification and art, the lack of working examples to meet the scope of the claims, and the lack of predictability provided by the specification or art for the diseases encompassed by the method, it is the conclusion that undue experimentation would be required to use the invention as claimed.
Response to Remarks - Method of Treating, Preventing, or Ameliorating the Effects of a Disease Associated with PTP1B
Applicant’s remarks regarding the scope of enablement rejection over claim 13 have been reviewed. Applicant appears to point to the amendments to the claim as remedying the rejection. Applicant also points to references which allegedly establish “that downregulating PTP1B using antisense oligonucleotides and other inhibitors of PTP1B production was able to suppress the markers of type 2 diabetes, obesity, and various solid tumor cancers and slow down disease.” Applicant indicates that these references provide predictability for the instantly claimed method.
The mechanism of action for the instant antisense oligomers differs from the PTP1B inhibitors in the references disclosed by Applicant. The references describe knocking down expression of PTP1B using shRNA, RNase-H based antisense oligomers, or inhibiting PTP1B with a specific small molecule inhibitor. None of the references employ a splice skipping antisense oligomer, or characterize the consequence of inducing alternative splicing of PTPN1 pre-mRNA. Claim 13 employs antisense oligomers which induce “alternative splicing of PTPN1 pre-mRNA through exon 2 skipping.” Based on the specification, the alternatively spliced PTPN1 mRNAs produce proteins which lack at least exon 2, a portion of exon 3, and exons 4-7, which "may generate a non-functional PTP1B protein" ([0029]). Indeed, the specification provides evidence that exon-skipped PTPN1 mRNAs are produced as a result of select antisense oligomers (see for example, Figs. 8-9), and show that PTP1B protein is produced following administration of two antisense oligomers encompassed by the claim (Fig. 16A-B).
Examiner acknowledges that the amount of PTP1B protein is reduced by these two antisense oligomers (Fig. 16B). However, there is no evidence that establishes that any antisense oligomer encompassed by the claim reduces the overall amount of PTP1B protein without producing truncated, non-functional PTP1B proteins. The working examples and mechanism of action described in the specification support that the exon-skipped PTPN1 mRNAs are produced, and that non-functional PTP1B proteins lacking exons 3-7 are produced therefrom. The references cited in each of the prior actions and above provide substantial evidence that promoting the formation of such truncated, non-functional PTP1B proteins may actually promote cancer and features of metabolic disease, i.e., the opposite effects of the claimed method. The remarks fail to address the teachings of the references cited in the prior actions and above. The remarks also fail to provide evidence that the encompassed antisense oligomers would not produce the truncated, non-functional PTP1B proteins described by the prior art. Taken together, there remains insufficient evidence to support that an antisense oligomer encompassed by the claim would treat the specifically recited solid cancers, type 2 diabetes, or obesity. The rejection is maintained and modified, accordingly.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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