DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of E7766 as the species of STING agonist in the reply filed on 7 August 2026 is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed 8 March 2024 is considered, initialed, and attached hereto.
Claim Status
Claims 46-75 are pending and under examination.
Claims 1-45 are canceled.
Claim Interpretation
Claim 46 (and by dependency claims 47-75) recites “reference […] DNA sequences” with regard to TMEM173 V48V (rs7447927), TLR6 S249P (rs5743810), and TLR10 I775V (rs4129009). In the specification, paragraph [44] states that “the term “wild-type allele, “reference allele” or “standard allele” refers to the nucleic acid sequence of the allele most commonly found in the human population”. Furthermore, paragraph [53] states that “the term “human STING gene” (STING gene also being referred to as “TMEM173”) […] comprises or consists of the nucleotide sequence of SEQ ID NO: 2”, paragraph [60] states that “the wild-type human TLR6 gene comprises or consists of the nucleotide sequence of SEQ ID NO: 6”, paragraph [65] states that “the wild-type human TLR10 gene comprises or consists of the nucleotide sequence of SEQ ID NO: 10, and Table 4 on page 38 states that the reference allele for TMEM173 (rs7447927) is C, for TLR6 (rs5743810) is T, and for TLR10 (rs4129009) is A.
However, the RefSNP reports for rs7447927, rs5743810, and rs4129009 on dbSNP, accessed from Wayback Machine snapshots captured 19 October 2019, 25 September 2019, and 23 September 2019, respectively, which are provided with this Office Action, identify rs7447927 as representing a C>G or C>T variation in the plus strand, rs5743810 as representing an A>G variation in the plus strand, and rs4129009 as representing a T>A, T>C, or T>G variation in the plus strand. Since these dbSNP pages also identify that the sense strand of the TMEM173, TLR6, and TLR10 genes are the minus strand, Examiner interprets the alleles provided on Table 4 of page 38 of the instant specification as referring to the nucleotide on the minus strand, which brings the definitions provided by the application in Table 4 for the rs5743810 and rs4129009 variants into agreement with the art-recognized definition of those rs #’s on dbSNP. However, for rs7447927, the minus strand in dbSNP carries a G for the reference sequence, unlike the C specified in the instant specification in Table 4. Notably, the RefSNP report for rs7447927 on dbSNP identifies that some sub populations and global population studies, such as African and East Asian populations and the Global population of the 1000Genomes study, have the C allele on the plus strand (so G allele on the minus strand) as the most frequent allele, whereas other sub populations and global population studies, such as European populations and the Global population of the gnomAD - Genomes study, have the G allele on the plus strand (so the C allele on the minus strand) as the most frequent allele. This variation in which allele is most frequent across studies and populations appears to explain this discrepancy between the dbSNP definition and the definition provided in the application. Because Applicant is entitled to be their own lexicographer, the definition provided in the application is used for interpretation of the claims. Therefore, for the purpose of examination, the reference alleles for rs7447927, rs5743810, and rs4129009, are interpreted as being the alleles that have C, T, and A on the minus strand at the respective rs# site. This interpretation applies to claims 46 and 50 that directly recite reference DNA sequences or reference for these rs #’s as well as claims 47-75 that depend from them.
Regarding claim 46 (and by dependency claims 47-75), the recited rs# sites rs7447927, rs5743810, and rs4129009. Though the specification recites in paragraph [72] that the term “patient” patient may “refer to any animal, such as any mammal”, rs7447927, rs5743810, and rs4129009 are specific to humans (Homo sapiens) (this is evidenced by the respective dbSNP reports that are provided with this Office Action). Because claim 46 requires that the patient carries specific genotypes at some combination of rs7447927, rs5743810, and rs4129009, the term “patient” in claims 46-75 is interpreted as referring only to humans.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
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 49, 51-52, and 61 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.
Claim 49 recites the limitation "wherein the patient’s genotype for single nucleotide variant(s) rs7447927, rs5743810, and/or rs4129009 is determined by" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim, because neither claim 49 nor claim 46 on which claim 49 depends recites a determination of the patient’s genotype. If claim 49 were amended to depend upon claim 47, then claim 47’s recitation of a step of “determining from the sample the patient’s genotype for single nucleotide variant(s) rs7447927, rs5743810, and/or rs4129009” would provide antecedent basis for this limitation.
Claim 51 recites the limitation "the upper aerodigestive tract" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 52 recites the limitation "the lip, buccal mucosa, floor of mouth, oral cavity, hard palate, base of tongue, oral tongue, tonsil, oropharynx, salivary gland, gallbladder, esophagus, stomach, and/or biliary tract" in lines 1-3. There is insufficient antecedent basis for this limitation in the claim.
Claim 61 recites the limitation "the tumor" in line 1. There is insufficient antecedent basis for this limitation in the claim, since it is unclear whether this recitation refers to the solid tumor recited in lines 1-2 of claim 60 upon which claim 61 depends or any other tumor of the cancer in the patient.
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 46-55 and 59-75 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.
Claim 46, upon which claims 47-55 and 59-75 depend, describes a method of treating a cancer in a patient, comprising administering a therapeutically effective amount of STING agonist. While the instant specification is sufficient to establish possession of the method of claim 46 using E7766 as the STING agonist, it is not sufficient to establish possession of the method of claim 46 using any STING agonist.
MPEP §2163 states:
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 (see i)(A) above), reduction to drawings (see i)(B) above), 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 (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.")
Applicant discloses in Example 2 ([119]) that a patient with esophageal cancer was treated with the STING agonist Compound 1, which is the diammonium salt of E7766 ([32]). Applicant also discloses other compounds that are STING agonists in paragraph [91] of the specification and that these other compounds are in clinical trials ([05]). The wide variety of compounds that are STING agonists disclosed in [05] and [91] of the specification illustrates the breadth of the genus of STING agonists that is claimed and their use in clinical trials illustrates the unpredictability in knowing whether a STING agonist can be administered for treating cancer. Importantly, the claimed genus of STING agonists encompasses not just currently known STING agonists, such as those in [05], but also any that may be discovered in the future regardless of their structural or mechanical similarities or differences to E7766 and the other STING agonist compounds disclosed in the application. Because a STING agonist is defined broadly as encompassing any “agent that may act directly on STING or an upstream or downstream component of the cGAS-STING pathway to provide an agonist effect” in the instant specification ([28]), the genus further includes compounds that provide an agonist effect through action on components of the cGAS-STING pathway that are discovered in the future. Therefore, one of ordinary skill in the art would not be able to reasonably say that the Applicant possessed a representative number of species that reflects the variation of the genus of STING agonists.
The factual inquiry now turns on whether there is a known or disclosed structure-function correlation that would disclose the genus of STING agonists. Due to the definition in the application of STING agonists as those compounds that act on STING or upstream or downstream components of the cGAS-STING pathway to provide an agonist effect, the genus of STING agonists encompasses various compounds that act on different proteins in the cGAS-STING pathway to exert the agonist effect. Because protein structure varies drastically among components of the cGAS-STING pathway (for example, compare the cGAS structure in Figure 2 of Zhou et al. with the STING C-terminal domain (CTD) structure in Figure 1 of Shang, which are presented below this paragraph in Exemplary Figures 1 and 2; Zhou et al. “Structure of the human cGAS–DNA complex reveals enhanced control of immune surveillance” Cell 174(2), pages 300-311 (2018); Shang et al. “Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP” Nat Struct Mol Biol 19(7), pages 725-727 (2012)), one of ordinary skill in the art would expect that compounds capable of interacting with such proteins to yield an agonist effect would also require drastically varying structures in order to achieve the STING agonist function. Therefore, there is no single structural feature disclosed in the art or application that confers the claimed function of a STING agonist as broadly encompassed by the claimed genus of STING agonists.
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Exemplary Figure 1: Excerpt of Figure 2 from Zhou et al. 2018 illustrating the structure of cGAS.
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Exemplary Figure 2: Figure 1 of Shang et al. 2012 illustrating the structure of STING CTD.
In conclusion, there are insufficient representative species in the art and in the disclosure of the specification to represent the full breadth of the claimed invention according to claims 46-55 and 59-75. Furthermore, a structure-function correlation is not shown in the specification or art to account for the broad variation of the genus of STING agonists as claimed. Note that claims 56-58 are not rejected because they limit the claimed method to the specific species of STING agonist, E7766. Thus, claims 46-55 and 59-75 are rejected under 35 U.S.C. 112(a) for failing to comply with the written description requirement.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 46-54, 56-57, and 64-75 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson et al. (US 2022/0211848, effectively filed 13 November 2020), herein Anderson, in view of Lubbers et al. (“Association of homozygous variants of STING1 with outcome in human cervical cancer”, Cancer Sci 112(1), pages 61-71 (2020)), herein Lubbers, and in view of Sun et al. (“Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk” J Natl Cancer Inst 97(7), pages 525-532 (2005)), herein Sun.
Regarding claim 46, Anderson teaches a method of treating a cancer in a patient, comprising administering a therapeutically effective amount of STING agonist to the patient (“a method of preventing or treating a subject afflicted with a cancer comprising administering to the subject a therapeutically effective amount of an agent” [0010]; “In some embodiments, the agent is a STING agonist” [0012]).
However, Anderson does not explicitly teach that the patient is specifically a patient who carries: (i) reference or heterozygous DNA sequences for TMEM173 V48V (rs7447927) and reference or homozygous DNA sequences for TLR6 S249P (rs5743810); or (ii) reference or heterozygous DNA sequences for TMEM173 V48V (rs7447927) and reference DNA sequences for TLR10 I775V (rs4129009). Notably, Anderson also does not exclude such patients and the method of claim 46 does not require any active steps involving the genotype of the patients (such as a step of determining the genotype of the patient for a specific rs# site). This deficiency is made up for in the teachings of Lubbers and Sun.
Regarding claim 46, Lubbers teaches people that have reference or heterozygous sequences at rs7447927 (“rs7447927 (V48V, c.144C > G)” page 62 left column paragraph 2; Figure 3 teaching genotypes WT/WT and WT/VAR at rs7447927) and further teaches that identification of STING variants such as rs7447927 may be associated with antitumor immunity and the effectiveness of STING agonist therapies (“Studies are currently ongoing to induce STING-mediated immunity, either directly via eg STING agonists or indirectly through radiotherapy or inhibition of the DNA damage repair pathway. As we speculate that homozygous variants of STING are associated with impaired antitumor immunity and fail to induce the activation of tumor-reactive CD8+ T cells, we hypothesize that STING-inducing therapy may not be effective in patients with these variants” page 70 right column paragraph 1).
Regarding claim 46, Sun teaches people that have reference or heterozygous sequences at rs5743810 or reference sequences at rs4129009 (Table 2 page 528, rows reciting “744C/T (rs5743810)” and “2322A/G (rs4129009)”; Table 3 page 529, row reciting “744C/T” in the SNP column with the number of case and control subjects with TT, CT, and CC genotypes, row reciting “2322A/G” in the SNP column with the number of case and control subjects with AA, GA, and GG genotypes) and further teaches an association between mutation at rs4129009 and prostate cancer risk (Table 2). Therefore, in combination with the teachings of Lubbers and Anderson, one of ordinary skill in the art would understand that patients in the method of Anderson may include patients with reference or heterozygous DNA sequences for rs7447927 as well as either (a) reference or heterozygous DNA sequences for rs5743810 or (b) reference DNA sequences for rs4129009.
Regarding claim 47, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Lubbers further teaches obtaining a biological sample from the patient and determining the patient’s genotype for single nucleotide variant rs7447927 (“frozen tissue samples and cervical epithelial scrapings were collected […] RNA was isolated […] cDNA was synthesized” page 62 right column paragraph 2; “STING1 cDNA was isolated through PCR amplification, followed by gel extraction and Sanger sequencing […] The following six STING1 single-nucleotide substitutions were included for analysis: V48V” page 62 right column paragraph 3; Figure 3 showing various outcomes measured for patients that were determined as WT/WT, WT/VAR, or VAR/VAR at rs7447927) and concludes that the V48V mutation at rs7447927 may be a useful biomarker in cervical cancer (“Homozygous V48V was found to be individually prognostic and may be investigated as a novel, surrogate prognostic biomarker in cervical cancer” page 70 right column paragraph 4).
Regarding claim 48, the combination of Anderson, Lubbers, and Sun teaches the method of claim 47 (see 35 U.S.C. 103 rejection of claim 47 above), and Anderson further teaches the identification of biomarkers from biological samples comprising a buccal sample, a blood sample, and/or a tumor sample (“determining a copy number, amount, and/or activity of at least one biomarker listed in Table 1 and/or Table 2 in a subject sample” [0023]; “in some embodiments, the sample comprises cells, serum, peritumoral tissue, and/or intratumoral tissue” [0026]; “a biological sample, e.g., a sample containing tissue, whole blood, serum, plasma, buccal scrape” [0097]).
Regarding claim 49, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Lubbers further teaches determining the patients genotype for single nucleotide variant rs7447927 by DNA variant testing comprising polymerase chain reaction (PCR) (“STING1 cDNA was isolated through PCR amplification, followed by gel extraction and Sanger sequencing […] The following six STING1 single-nucleotide substitutions were included for analysis: V48V” page 62 right column paragraph 3 in Section titled ‘2.2 | Analysis of STING1 expression and allelic variance’, note that the variant testing that is ultimately determined by Sanger sequencing includes PCR).
Regarding claim 50, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above). As discussed with regard to claim 46 above, Lubbers teaches patients that are reference for rs7447927 (Figure 3) and Sun teaches patients that are reference for rs5743810, heterozygous for rs5743810, or reference for rs4129009 (Table 3). Therefore, one of ordinary skill in the art would understand that patients in the method of Anderson may be (i) reference for rs7447927 and reference for rs5743810; (ii) reference for rs7447927 and heterozygous for rs5743810; or (iii) reference for rs7447927 and reference for rs4129009.
Regarding claim 51, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Anderson further teaches the method wherein the cancer comprises a cancer of the upper aerodigestive tract (“In some embodiments, the cancer is selected from the group consisting of […] head and neck cancer, biliary tract cancer […] esophageal cancer” [0020]).
Regarding claim 52, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Anderson further teaches the method wherein the cancer comprises a cancer of the lip, buccal mucosa, floor of mouth, oral cavity, hard palate, base of tongue, oral tongue, tonsil, oropharynx, salivary gland, gallbladder, esophagus, stomach and/or biliary tract (“In some embodiments, the cancer is selected from the group consisting of […] head and neck cancer, biliary tract cancer […] esophageal cancer” [0020]).
Regarding claim 53, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Anderson further teaches the method wherein the cancer comprises a head and neck squamous cell carcinoma (HNSCC) or an esophageal cancer (“In some embodiments, the cancer is selected from the group consisting of […] squamous cell carcinoma, head and neck cancer […] esophageal squamous cell carcinoma […] esophageal cancer” [0020]).
Regarding claim 54, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Anderson further teaches the method wherein the cancer is a recurrent cancer (“In some embodiments, the cancer is a relapsed cancer” [0020]).
Regarding claims 56-57, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Anderson further teaches the method wherein the STING agonist comprises E7766 (“In some embodiments, the agent is a STING agonist […] macrocycle-bridged STING agonist E7766” [0012]).
Regarding claim 64, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Anderson further teaches the method the STING agonist is administered to the patient in combination with at least one additional therapy (“In some embodiments, the method further comprises administering to the subject, or contacting the cancer cell with, an additional cancer therapy” [0019]).
Regarding claim 65, the combination of Anderson, Lubbers, and Sun teaches the method of claim 64 (see 35 U.S.C. 103 rejection of claim 64 above), and Anderson further teaches the method wherein the at least one additional therapy comprises administering a checkpoint inhibitor (“In some embodiments, the additional cancer therapy is selected from the group consisting of immunotherapy […] In some embodiments, the immunotherapy inhibits an immune checkpoint” [0019]).
Regarding claim 66, the combination of Anderson, Lubbers, and Sun teaches the method of claim 65 (see 35 U.S.C. 103 rejection of claim 65 above), and Anderson further teaches the method wherein the checkpoint inhibitor targets programmed death-1 pathway (PD1), programmed death-ligand 1 pathway (PDL1), and/or cytotoxic T-lymphocyte-associated antigen 4 pathway (CTLA4) (“In some embodiments, the immune checkpoint is selected from the group consisting of CTLA-4, PD-1, PD-L1” [0019]).
Regarding claim 67, the combination of Anderson, Lubbers, and Sun teaches the method of claim 66 (see 35 U.S.C. 103 rejection of claim 66 above), and Anderson further teaches the method wherein the checkpoint inhibitor comprises an anti-PD1 antibody (“In one embodiment, anti-PD-1 antibodies […] are used to inhibit immune checkpoints” [0125]).
Regarding claim 68, the combination of Anderson, Lubbers, and Sun teaches the method of claim 67 (see 35 U.S.C. 103 rejection of claim 67 above), and Anderson further teaches that pembrolizumab is an anti-PD1 antibody (“pembrolizumab (anti-PD-1)” [0006]).
Regarding claim 69, the combination of Anderson, Lubbers, and Sun teaches the method of claim 66 (see 35 U.S.C. 103 rejection of claim 66 above), and Anderson further teaches the method wherein the checkpoint inhibitor comprises an anti-PDL1 antibody (“In one embodiment […] anti-PD-L1 antibodies […] are used to inhibit immune checkpoints” [0125]).
Regarding claim 70, the combination of Anderson, Lubbers, and Sun teaches the method of claim 66 (see 35 U.S.C. 103 rejection of claim 66 above), and Anderson further teaches the method wherein the checkpoint inhibitor comprises an anti-CTLA4 antibody (“In yet another embodiment, immunomodulatory antibodies or protein are used. For example, […] anti-CTLA4 antibody” [0427]).
Regarding claim 71, the combination of Anderson, Lubbers, and Sun teaches the method of claim 70 (see 35 U.S.C. 103 rejection of claim 70 above), and Anderson further teaches the method wherein the anti-CTLA4 antibody comprises ipilimumab (“In yet another embodiment, immunomodulatory antibodies or protein are used. For example, […] ipilimumab” [0427]).
Regarding claim 72, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Anderson further teaches the method wherein the treatment reduces or inhibits growth of a tumor in the patient, as compared to the growth of the tumor prior to treatment (“In some embodiments, the agent reduces the number of proliferating cancer cells and/or reduces the volume or size of a tumor comprising the cancer cells” [0018]; “Tumor response may be assessed in a neoadjuvant or adjuvant situation where the size of a tumor after systemic intervention can be compared to the initial size and dimensions” [0449]; Fig. 22A, note that ADUS-100 (also called ADU-S100) is a STING agonist per [0568], COMBO includes treatment with ADU-S100 and BTZ, and CNT is the control with no treatment).
Regarding claim 73, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Anderson further teaches the method wherein the treatment reduces the size of a tumor in the patient by at least 5% as compared to the size of the tumor prior to treatment ([0018] and [0449] as discussed regarding claim 72 above; Fig. 22A, note that the COMBO includes treatment with the STING agonist ADU-S100 and results in a decrease from just under 200 mm3 to 0 mm3 between 1 and 4 days after treatment which is a greater than 5% reduction in size).
Regarding claim 74¸ the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above), and Anderson further teaches that treatment with a STING agonist increases or decreases the expression or activity of at least one cytokine or chemokine in the patient (“the synthetic cyclic dinucleotide STING agonist ADU-S100 […] increased transcription of IFNA1 and IFNB1 (FIG. 31B)” [0568]; “FIG. 31B qRT-PCR analysis of IFNA1 and IFNB1 mRNAs in H929 cells treated with BTZ (5 nM), STING agonist (10 uM), or the combination (COMBO)” [0072]; Fig. 31B showing IFNA1 and Fig. 31B (cont.) showing IFNB1; note that both ADUS-100 and COMBO treatments fall within the scope of the claimed treatment). Though Anderson teaches that the significant changes in IFNA1 and IFNB1 when treated with treatments that include a STING agonist are with regard to their comparison to the “-“ untreated control, one of ordinary skill in the art would understand that the ”-“ untreated control is representative of the expression that would be present prior to treatment.
Regarding claim 75, the combination of Anderson, Lubbers, and Sun teaches the method of claim 74 (see 35 U.S.C. 103 rejection of claim 74 above), and Anderson further teaches that the at least one cytokine or chemokine comprises IFNα, IFNβ, IFNγ, IP-10, MCP-1, MCP-1b, IL-6, and/or TNFα (Fig. 31B and Fig. 31B (cont.); “FIG. 31B qRT-PCR analysis of IFNA1 and IFNB1 mRNAs in H929 cells treated with BTZ (5 nM), STING agonist (10 uM), or the combination (COMBO)” [0072]; note that IFNA is interpreted as IFNα and IFNB is interpreted as IFNβ).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the genotype of reference or heterozygous DNA sequences for rs7447927 as taught by Lubbers for the genotype of the patient at rs7447927 that has no restrictions on their genotype in the method of Anderson (MPEP §2143 I. B.). Furthermore, one of ordinary skill in the art would also be motivated to combine the teachings of Lubbers with the method of Anderson because Lubbers teaches that determining a patient’s genotype for variants of STING such as rs7447927 provides the advantage of being useful for differentiating patients that may receive less benefit from STING-inducing therapies. One of ordinary skill in the art could have performed this substitution and would have found the results of this substitution predictable because the patient having a specific genotype at a SNP site would not be expected to impair the ability for a therapeutically effective amount of a STING agonist to be administered to a patient. Therefore, the combination of Anderson and Lubbers would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the genotype of either reference or heterozygous DNA sequences for rs5743810 or reference DNA sequences for rs4129009 as taught by Sun for the genotype of the patient at either rs5743810 or rs4129009, respectively, in the method of the combination of Anderson and Lubbers (MPEP §2143 I. B.). One of ordinary skill in the art could have performed this substitution and would have found the results of this substitution predictable because the patient having a specific genotype at a SNP site would not be expected to impair the ability for a therapeutically effective amount of a STING agonist to be administered to a patient. Therefore, the invention as a whole of claims 46-54, 56-57, and 64-75 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claims 55 and 59-63 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson et al. (US 2022/0211848, effectively filed 13 November 2020), herein Anderson, in view of Lubbers et al. (“Association of homozygous variants of STING1 with outcome in human cervical cancer”, Cancer Sci 112(1), pages 61-71 (2020)), herein Lubbers, and in view of Sun et al. (“Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk” J Natl Cancer Inst 97(7), pages 525-532 (2005)), herein Sun, as applied to claims 46-54, 56-57, and 64-75 above, and further in view of Eisai Inc. (“Study of Intratumorally Administered Stimulator of Interferon Genes (STING) Agonist E7766 in Participants With Advanced Solid Tumors or Lymphomas – INSTAL-101” ClinicalTrials.gov ID NCT04144140, version 6 submitted 19 August 2020 and “Last Update Posted” 21 August 2020), herein Eisai.
Regarding claim 55, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above). However, neither Anderson, Lubbers, nor Sun teach the method wherein the cancer is a metastatic cancer. This deficiency is made up for in the teachings of Eisai.
Regarding claim 55, Eisai teaches administering the STING agonist E7766 to patients for treating cancer wherein the cancer includes metastatic cancer (“E7766 will be administered intratumorally in participants with advanced solid tumors or lymphomas” page 6, Detailed Description section; “Exclusion Criteria: […] 4. Brain metastases that are untreated or in the posterior fossa or involve the meninges. Participants with stable or progressing brain metastases (Except in the posterior fossa or involving the meninges) previously treated with brain stereotactic radiotherapy (SRT), whole-brain radiotherapy (WBRT) and/or surgery are allowed as long as the participant is asymptomatic neurologically and does not require immediate local intervention” page 13, note that Eisai explicitly permits the treatment of certain patients with metastases, which imply metastatic cancer).
Regarding claim 59, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above). Eisai teaches administering the STING agonist E7766 to patients for treating cancer (see 35 U.S.C. 103 rejection of claim 55 above), and further teaches the administration wherein the STING agonist is administered to the patient intratumorally via an intra-tumoral injection (“E7766 will be administered intratumorally in participants” page 6, Detailed Description; “Intratumoral injection” page 6, Keywords; “E7766, solution, intratumorally” page 7 Assigned Interventions; “Participants must have a minimum of one injectable lesion” page 12 Criteria).
Regarding claim 60, the combination of Anderson, Lubbers, Sun, and Eisai teaches the method of claim 59 (see 35 U.S.C. 103 rejection of claim 59 above), and Eisai further teaches that the injection is administered into a solid tumor (“Participants must have a minimum of one injectable lesion […] An injectable lesion is defined as being measurable (defined below) […] Measurable lesions are: 1. Solid tumors” page 12 Criteria).
Regarding claim 61, the combination of Anderson, Lubbers, Sun, and Eisai teaches the method of claim 60 (see 35 U.S.C. 103 rejection of claim 60 above), and Eisai further teaches that the tumor has a long-axis diameter of at least 1 centimeter (“Measurable lesions are: 1. Solid tumors: At least 1 lesion of greater than or equal to (>=1) cm by longest axial diameter […] which is serially measurable according to modified Response evaluation criteria in solid tumors (RECIST) 1.1 using CT/MRI or photograph” page 12 Criteria).
Regarding claim 62, the combination of Anderson, Lubbers, and Sun teaches the method of claim 46 (see 35 U.S.C. 103 rejection of claim 46 above). Eisai teaches administering the STING agonist E7766 to patients for treating cancer (see 35 U.S.C. 103 rejection of claim 55 above), and further teaches the administration wherein the STING agonist is administered to the patient into a lymph node via an intra-lymph node injection (“E7766 will be administered intratumorally in participants” page 6, Detailed Description; “Participants must have a minimum of one injectable lesion […] An injectable lesion is defined as being measurable (defined below) […] Measurable lesions are: […] 2. Lymphoma: At least 1 lymph node” page 12 Criteria).
Regarding claim 63, the combination of Anderson, Lubbers, Sun, and Eisai teaches the method of claim 62 (see 35 U.S.C. 103 rejection of claim 62 above), and Eisai further teaches that the lymph node has a short-axis diameter of at least 1.5 centimeters (“>=1.5 cm short axis diameter if a nodal lesion, which is serially measurable according to modified Response evaluation criteria in solid tumors (RECIST) 1.1 using CT/MRI or photograph” page 12 Criteria).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the metastatic cancer taught by Eisai for the cancer in the method taught by the combination of Anderson, Lubbers, and Sun (MPEP §2143 I. B.). One of ordinary skill in the art could have performed this substitution and would have found the results of this substitution predictable because Anderson teaches that a wide variety of cancers can be treated using the STING agonist (see Anderson [0020]) and contemplates metastasis of the cancer (“cancer is also “inhibited” if recurrence or metastasis of the cancer is reduced, slowed, delayed, or prevented” Anderson [0159]) and because Eisai teaches treatment using one of the same STING agonists as Anderson, E7766. Therefore, the invention as a whole of claims 55 and 59-63 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claim 58 is rejected under 35 U.S.C. 103 as being unpatentable over Anderson et al. (US 2022/0211848, effectively filed 13 November 2020), herein Anderson, in view of Lubbers et al. (“Association of homozygous variants of STING1 with outcome in human cervical cancer”, Cancer Sci 112(1), pages 61-71 (2020)), herein Lubbers, and in view of Sun et al. (“Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk” J Natl Cancer Inst 97(7), pages 525-532 (2005)), herein Sun, as applied to claims 46-54, 56-57, and 64-75 above, and further in view of Jiang et al. (Foreign Patent Document Cite No 3 in IDS filed 8 March 2024)(WO 2021/003279, published 7 January 2021), herein Jiang.
Regarding claim 58, the combination of Anderson, Lubbers, and Sun teaches the method of claim 57 (see 35 U.S.C. 103 rejection of claim 57 above). However, neither Anderson, Lubbers, nor Sun teach the method wherein the STING agonist comprises the diammonium salt of E7766. This deficiency is made up for in the teachings of Jiang.
Regarding claim 58, Jiang teaches that E7766 is a compound for treating cancer and specifically teaches the use of the diammonium salt of E7766 for treatment of cancer (“the diammonium salt of E7766, shown below, has been reported for use in treatment of cancer” page 1 paragraph 2).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the diammonium salt of E7766 taught by Jiang for E7766 as the STING agonist in the cancer treatment taught by the combination of Anderson, Lubbers, and Sun (MPEP §2143 I. B.). One of ordinary skill in the art could have performed this substitution and would have found the results of this substitution predictable because both are based on the same structure of E7766, both are taught for the purpose of treating cancer, and because Jiang teaches that the diammonium salt of E7766 is a pharmaceutically acceptable salt of E7766 (Jiang page 6 paragraph 4). Therefore, the invention as a whole of claim 58 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
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 46-75 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 or 2 of U.S. Patent No. 12,251,394, herein ‘394, in view of a combination of Anderson, Lubbers, Sun, and Eisai (as referenced in the 35 U.S.C. 103 rejections above).
Regarding instant claim 46, claim 1 of ‘394 recites a method of treating a specific cancer, bladder cancer, comprising administering to a patient an effective among of Compound 1. Note that Compound 1 is identical to E7766 as disclosed in the instant specification, so claim 1 of ‘394 comprises administering to a patient an effective of amount of a specific STING agonist. However, ‘394 does not recite in any claims the specific combinations of genotypes that the patient carries at rs7447927 and either rs5743810 or rs4129009 as required by instant claim 1. This deficiency is made up for by the teachings of Lubbers and Sun.
Regarding instant claim 46, Lubbers teaches patients that have reference or heterozygous sequences at rs7447927 (see discussion of Lubbers in the 35 U.S.C. 103 rejection of claim 46 above).
Regarding instant claim 46, Sun teaches people that have reference or heterozygous sequences at rs5743810 or reference sequences at rs4129009 (see discussion of Sun in the 35 U.S.C. 103 rejection of claim 46 above).
Regarding instant claims 47 and 49, Lubbers teaches all additional limitations of these claims as discussed in the 35 U.S.C. 103 rejections of claims 47 and 49 above.
Regarding instant claim 50, Lubbers and Sun in combination teach all additional limitations of instant claim 50 as discussed in the 35 U.S.C. 103 rejection of claim 50 above.
Regarding instant claims 48, 51-54, and 64-75, Anderson teaches all additional limitations of these claims as discussed in the 35 U.S.C. 103 rejections of claims 48, 51-54, and 64-75 above.
Regarding instant claims 56-57, claim 1 of ‘394 recites Compound 1 or a pharmaceutically acceptable salt thereof, which as discussed with regard to instant claim 46 above, is E7766.
Regarding instant claim 58, claim 2 of ‘394 depends up claim 1 of ‘394 and further recites that the pharmaceutically acceptable salt is a diammonium salt, which is the same as the diammonium salt of E7766 claimed in instant claim 58.
Regarding instant claims 55 and 59-63, Eisai teaches all additional limitations of these claims as discussed in the 35 U.S.C. 103 rejections of claims 55 and 59-63 above.
Similar to Anderson, claim 1 of ‘394 recites treating cancer in a patient with a STING agonist. Therefore, for the same reasons discussed in the 35 U.S.C. 103 rejection of claims 46-54, 56-57, and 64-75 that it would be obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute a patient having the genotypes taught by Lubbers and Sun for the generic patient in the method of Anderson, it would also be obvious to one of ordinary skill in the art to substitute a patient having the genotypes taught by Lubbers and Sun for the generic patient in the method of claim 1 of ‘394. Therefore, claims 46-47, 49-50, and 56-57 are obvious variants of claim 1 of ‘394 and claim 58 is an obvious variant of claim 2 of ‘394.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the generic STING agonist for treating cancer in the method taught by Anderson for the Compound 1, which is the STING agonist E7766, using for treating cancer in the method of claim 1 of ‘394 (MPEP §2143 I. B.). One of ordinary skill in the art could have performed this substitution and would have found the results of this substitution predictable because both compounds are used for the treatment of cancer. Therefore, claims 48, 51-54, and 64-75 are obvious variants of claim 1 of ‘394.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to further combine the combination of claim 1 of ‘394, Lubbers, Sun, and Anderson with the teachings of Eisai for the same reasons discussed in the 35 U.S.C. 103 rejection of claims 55 and 59-63 above because the same teachings of Eisai and Anderson apply. Therefore, claims 55 and 59-63 are obvious variants of claim 1 of ‘394.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Guirado et al. (“Association between C13ORF31, NOD2, RIPK2 and TLR10 polymorphisms and urothelial bladder cancer” Hum Immonol 73(6), pages 668-672 (2012)) teaches an association between mutations at rs4129009 and tumor infiltration stage.
Semlali et al. (“Novel sequence variants in the TLR6 gene associated with advanced breast cancer risk in the Saudi Arabian population” PLoS One 13(11), e0203376 (2018)) teaches an association between mutations at rs5743810 and breast cancer risk.
Semlali et al. (“Toll-like receptor 6 expression, sequence variants, and their association with colorectal cancer risk” J Cancer 10(13), pages 2969-2981 (2019)) teaches an association between mutations at rs5743810 and colorectal cancer risk.
Conclusion
Claims 46-75 are rejected. Claims 1-45 are canceled. No claims are allowed.
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/JEFFREY BELLAH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
