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 .
Claims Status
Claims 1-20 are pending and are examined on the merits.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Both Fig. 11 and Fig. 12A recite the sequence “GTTGTCGTTTTTTGTCGTT”. Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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.
Claim Rejections - 35 USC § 112
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.
Claim 13 is 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.
Claim 13 is drawn to the method of treating of claim 7 wherein the “effective amount” of the pharmaceutical composition is within the range of 0.1-20 mg/kg body weight. However, it is unclear to which therapeutic component/s in the pharmaceutical combination the claim is referring – i.e. is the claim drawn to 0.1-20 mg/kg of the “active pharmaceutical ingredient”, the “toll-like receptor agonist”, the “stimulator of interferon genes agonist”, the “pharmaceutically acceptable carrier”, every component individually, or a total dose of all components combined?
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 4, 10, and 19 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.
Scope of the claimed invention
Claims 4, 10, and 19 each require a toll-like receptor agonist comprising 70% sequence identity to SEQ ID NO: 31, allowing for variation in 5-6 nucleotides including substitutions, insertions, and deletions without limit to the position where these variations may occur or the resulting sequences. Accordingly, the claims are drawn to an extremely large genus of potential sequences limited only by the requirement that they function as TLR agonists.
State of the prior art
CpG-ODN comprising an identical sequence to instantly claimed SEQ ID NO: 31 is known in the art as “CpG-2722” and was previously described by Yeh et al. 2017 (Scientific reports, 7(1), 17297.; PTO-892). However, Yeh teaches the importance of the specific nucleotide sequence to the function of any given CpG-ODN and that “the number, position, spacing, and surrounding bases of the CpG-hexamer motifs” as well as the length of the CpG-ODN are all important factors contributing to its immunostimulatory activity (Pg. 3, ¶2). Yeh further teaches that even small changes to the underlying CpG-2722 sequence – such as a short 3 nucleotide truncation – resulted in a dramatic decrease in the ability of these CpG-ODNs to function (see, for example, comparisons to CpG-2726, CpG-2728, CpG-2729 in Fig. 2D-E). Accordingly, it was known in the art that even minor modifications to CpG-ODNs can have unpredictable impacts on the immunostimulatory capacity of these molecules.
Description of representative species in the specification
MPEP § 2163 states that 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.
The instant application discloses but a single species of CPG-ODN (CpG-2722; SEQ ID NO: 31; Fig. 12), which was employed in each of the disclosed examples. There is no disclosure of any other CpG sequence belonging to the claimed genus of 70% identity to SEQ ID NO: 31. In view of the immense breadth of the claims described above, one of ordinary skill in the art would not reasonably consider disclosure of a single species belonging to the claimed genus a “representative number of species”.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed immunostimulatory activity.
As stated above, the application discloses a single species of CpG-ODN. While it is apparent from the examples that CpG-2722 possesses the claimed TLR agonist activity, there is no discussion of which sequences are structurally critical to this function or what modifications can be made such that the agonist activity is maintained. As such, applicant has not sufficiently conveyed that they were in possession of the invention commensurate in scope with the claims given the large breadth of the claims, the known importance of a specific CpG sequence to its function, and the lack of guidance provided by the specification.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5-9, 11-18, and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cai et al. 2022 (Cancer Immunology, Immunotherapy, 71(7), 1597-1609.; PTO-892), herein “Cai”.
Regarding Claims 1-3, 5, 7-9, 11, 15, and 18, Cai teaches a method of treating cancer comprising administering a combination of CpG (i.e. a toll-like receptor agonist), cGAMP (i.e. a stimulator of interferon genes agonist), and an anti-OX40 antibody (i.e. an active pharmaceutical ingredient) (Abstract; Fig. 1). See, for example, Pg. 1605 § Discussion ¶1: “By administering an in situ injection of three drugs in combination, namely the TLR9 agonist CpG, agonistic anti-OX40 antibody and STING agonist cGAMP, we not only significantly slowed the growth of tumours at the injection site but also altered the growth of distant tumours”.
Further, regarding Claim 7, Cai teaches that the combined therapy resulted in increased cytokine production (i.e. inducing an immune response).
Regarding Claims 6 and 12, Cai teaches that the cyclic dinucleotide STING agonist is 2’3’-cGAMP (Pg. 1599; § Cell lines and reagents, ¶2).
Regarding Claim 13, Cai teaches the treated mice weighed approximately 20g (Fig. 3f) and were administered a dose of CpG, anti-OX40, and cGAMP at 50 µg/mouse, 30 µg/mouse, and 10 µg/mouse, respectively (Pg. 1599; § Tumour inoculation and animal experiment, ¶2). Accordingly, the mice received a dose of approximately 2.5 mg/kg CpG, 1.5 mg/kg anti-OX40, and 0.5 mg/kg cGAMP – or a total combined dose of 4.5 mg/kg.
Regarding Claim 14, Cai teaches the combined therapeutic is administered intratumorally (Pg. 1599; § Tumour inoculation and animal experiment, ¶2).
Regarding Claims 16-17, Cai teaches that the combined therapy can further comprise an anti-PD-1 antibody, which improves the efficacy of the therapeutic combination against PD-1 sensitive tumors (Pg. 1605 ¶1; Fig. 7c-e).
Regarding Claim 20, Cai teaches the combined therapy can be used to treat tumors derived from melanoma cell line B16 (§ Results, ¶1; Fig. 3 g-h, j).
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.
Claims 4, 10, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. 2022 (Cancer Immunology, Immunotherapy, 71(7), 1597-1609.; PTO-892), herein “Cai”, as applied to claims 1-3, 5-9, 11-18, and 20 above, and further in view of Chuang et al. 2019 (US 10246715 B1; PTO-892), herein “Chuang”.
The teachings of Cai are summarized above.
In addition, Cai teaches that the combination of CpG/anti-OX40/cGAMP outperforms each therapeutic individually as well as combined CpG/anti-OX40 without the cGAMP (Fig. 3).
Chuang teaches a CpG-ODN termed “CpG-2722” which comprises 100% identity with instant SEQ ID NO: 31 (See alignment below with Chuang SEQ ID NO: 2):
SEQ ID NO: 31 1 GTTGTCGTTTTTTGTCGTT 19
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Chuang SEQ2 1 GTTGTCGTTTTTTGTCGTT 19
Chuang teaches methods of inducing an immune response and treating cancer such as melanoma comprising administering the disclosed CpG-ODNs (Col. 2, lines 28-42).
Chuang teaches that unlike other CpG-ODNs which exhibit varying activity across different species (Col. 11, lines 53-670, CpG-2722 strongly activated TLR9 and cytokine production in humans, mice, and grouper (Fig. 8) and could therefore be a useful immunomodulatory adjuvant across a range of species (Co. 12, Lines 4-6).
It would have been obvious to one of ordinary skill in the art to substitute the CpG of the pharmaceutical composition and treatment method of Cai with the CpG-2722 taught by Chuang, resulting in a composition comprising a combination of CpG-2722, 2’3’-cGAMP, and anti-OX40. The skilled artisan would have been motivated to instead use CpG-2722 because Chuang teaches that CpG-2722 can be used to stimulate an immune response in a wider variety of species. There would have been a reasonable expectation of success because Cai teaches addition of cGAMP to a therapeutic comprising CpG dramatically improves its efficacy, and because Chuang teaches that CpG-2722 is a potent activator of human TLR9.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,246,715 in view of Cai et al. 2022 (Cancer Immunology, Immunotherapy, 71(7), 1597-1609.; PTO-892), herein “Cai”.
The claims of ‘715 are drawn to a TLR9 agonist CpG-ODN (claims 1-4), compositions comprising said CpG-ODN (claims 5-6 and 12-13), and methods of administering said CpG-ODN to induce an immune response and treat disease such as melanoma (claims 7-11) wherein the CpG-ODN comprises 100% identity to instantly claimed SEQ ID NO: 32 (claim 13; see alignment below).
SEQ ID NO: 31 1 GTTGTCGTTTTTTGTCGTT 19
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‘715 SEQ2 1 GTTGTCGTTTTTTGTCGTT 19
The claims of ‘715 are not drawn to a pharmaceutical composition further comprising a cyclic dinucleotide STING agonist and an additional active pharmaceutical ingredient. This deficiency is cured by Cai.
Regarding Claims 1-3, 5, 7-9, 11, 15, and 18, Cai teaches a method of treating cancer comprising administering a combination of CpG (i.e. a toll-like receptor agonist), cGAMP (i.e. a stimulator of interferon genes agonist), and an anti-OX40 antibody (i.e. an active pharmaceutical ingredient) (Abstract; Fig. 1). See, for example, Pg. 1605 § Discussion ¶1: “By administering an in situ injection of three drugs in combination, namely the TLR9 agonist CpG, agonistic anti-OX40 antibody and STING agonist cGAMP, we not only significantly slowed the growth of tumours at the injection site but also altered the growth of distant tumours”.
Further, regarding Claim 7, Cai teaches that the combined therapy resulted in increased cytokine production (i.e. inducing an immune response).
In addition, Cai teaches that the combination of CpG/anti-OX40/cGAMP outperforms each therapeutic individually as well as combined CpG/anti-OX40 without the cGAMP (Fig. 3).
Regarding Claims 6 and 12, Cai teaches that the cyclic dinucleotide STING agonist is 2’3’-cGAMP (Pg. 1599; § Cell lines and reagents, ¶2).
Regarding Claim 13, Cai teaches the treated mice weighed approximately 20g (Fig. 3f) and were administered a dose of CpG, anti-OX40, and cGAMP at 50 µg/mouse, 30 µg/mouse, and 10 µg/mouse, respectively (Pg. 1599; § Tumour inoculation and animal experiment, ¶2). Accordingly, the mice received a dose of approximately 2.5 mg/kg CpG, 1.5 mg/kg anti-OX40, and 0.5 mg/kg cGAMP – or a total combined dose of 4.5 mg/kg.
Regarding Claim 14, Cai teaches the combined therapeutic is administered intratumorally (Pg. 1599; § Tumour inoculation and animal experiment, ¶2).
Regarding Claims 16-17, Cai teaches that the combined therapy can further comprise an anti-PD-1 antibody, which improves the efficacy of the therapeutic combination against PD-1 sensitive tumors (Pg. 1605 ¶1; Fig. 7c-e).
Regarding Claim 20, Cai teaches the combined therapy can be used to treat tumors derived from melanoma cell line B16 (§ Results, ¶1; Fig. 3 g-h, j).
It would have been obvious to one of ordinary skill in the art to modify the method and composition of the claims of ‘715 to further comprise a cGAMP, anti-OX40, and anti-PD-1 according to the teachings of Cai. The skilled artisan would have been motivated by the teachings of Cai demonstrating improved immunostimulatory activity and anti-tumor efficacy of the combined CpG/cGAMP/antibody therapy relative to each therapeutic alone. There would have been a reasonable expectation of success because the CpG of Cai and that of ‘715 are both TLR9 agonists.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRYAN WILLIAM HECK whose telephone number is (703)756-4701. The examiner can normally be reached Mon-Fri 8:00am - 5:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRYAN WILLIAM HECK/ Examiner, Art Unit 1643
/GARY B NICKOL/ Primary Examiner, Art Unit 1643