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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/25/2026 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/25/2026 was filed after the mailing date of the final on 03/27/2026. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Status of the Claims
Claims 1, 5, 7-10, 16-20, 47-49, 54, and 59-61 are pending in this application. Claims 2-4, 6, 11-1, 21-46, 50-53, and 55-58 have been cancelled by applicant.
Claim Objections
Claims 1 and 54 are objected to because of the following informalities: “Pd-1” should be “PD-1”.
Appropriate correction is required.
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 17 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 17 recites a method of treatment of “hepatoma/ cholangio carcinoma” – since these are two different types of cancers and not interchangeable names of the same thing, it is unclear why they have been separated by a slash ‘/’. Does Applicant mean to treat cases presenting with “hepatoma or cholangio carcinoma” or cases presenting with “hepatoma and cholangio carcinoma”, or does applicant mean these to be independent alternatives in the list of cancers of claim 17. For the purposes of applying art, it will be assumed applicant intended the latter. Examiner suggests replacing slash ‘/’ with a comma ‘,’.
Claim 18 is not included in this rejection despite depending from claim 17, since it remedies the deficiencies of indefinite claim 17.
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.
Claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61 are rejected under 35 U.S.C. 103 as being unpatentable over Bartlett (WO 2018/176,099 – cited in IDS – previously cited) (“Bartlett”); in view of Jackson (WO 2012/037,612 – cited in IDS – previously cited) (“Jackson”); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019) – Pub. Date: May 10th, 2019) (“Sharma”).
Regarding claim 1, Bartlett discloses the compound INNA-011 below (page 50, line 5);
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in page 85 (entry 5). Bartlett teaches their compounds as TLR2 agonists (page 2-3).
Regarding claim 19, Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery (page 7, lines 10-12).
Regarding claim 61, Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
While Bartlett does not specifically teach: (i) their TLR2 agonist compound for the treatment of cancer; or (ii) co-administration of a CTLA-4 inhibitor; the teachings of Jackson and Sharma are relied upon for these disclosures.
Jackson’s invention is predicated on the observation that a TLR2 agonist such as Pam2Cys demonstrates the ability to raise an innate immune response in a subject (page 8, lines 20-22). Jackson discloses the TLR2 moiety comprises Pam2Cys conjugated to polyethylene glycol chain (PEG) (page 13, lines 14-15) and contemplates the use of a TLR2 moiety for treating cancer in a subject (see page 17, para. 4). Jackson provides a method for treating or preventing cancer by raising an innate immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a TLR2 moiety in solution. In some embodiments, administration of the TLR2 moiety inhibits the growth or spread of cancer (metastasis) (page 17, lines 19-27). The invention claims a method for treating a cancer, which can be caused by an infectious agent, including HPV, HCV, or Epstein Barr Virus (claims 15 and 16). Jackson also provides a pharmaceutical composition comprising an effective amount of a TLR2 moiety in solution together with a pharmaceutically acceptable carrier or excipient for treating or preventing a disease by raising an innate immune response in a subject (page 20, lines 15-17). Jackson’s compositions may be administered by any means known to those skilled in the art, including, but not limited to, intranasally, orally, and intravenously (page 20, lines 22-24). Jackson further discloses their compositions may include other physiologically active agents (page 20, lines 14-15).
Sharma teaches anti-CTLA-4 are widely accepted therapeutic options for many cancers (abstract). Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Bartlett’s TLR2 inhibitor INNA-011 shown above, for the treatment of cancer in a subject, in view of Jackson, in combination with an immunostimulant comprising an anti-CTLA-4 antibody, in view of Sharma. One of ordinary skill would have been motivated to do so in view of Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) and pharmaceutical compositions thereof as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and Sharma’s teaching that Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone. One of ordinary skill would have had a reasonable expectation of success in doing so in view of Jackson’s disclosure that their compositions comprising related TLR2 inhibitors may be administered with other active agents (reading on instantly claimed co-administration of CTLA-4 inhibitors); and Sharma’s teachings.
Applicant is advised that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art (In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).” See MPEP2144.06. It is therefore obvious to provide a mixture of the two agents.
Regarding claim 5, Jackson teaches a method of treatment of cancer. It flows from the art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding claim 7, Jackson teaches the use of a TLR2 moiety as defined herein for treating cancer in a subject; a method for treating or preventing cancer by raising an innate immune response in a subject comprising administering a composition comprising a TLR2 moiety in solution; and a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 8, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 10, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist. It flows from this art that identification of a subject who has a tumor capable of spreading (metastasizing) would occur prior to administration of any treatment of cancer.
Regarding claim 16, Barlett and Jackson in view of Sharma disclose the benefits of co-administering a CTLA-4 antibody with a TLR2 agonist, such as the instant compound.
Regarding claims 17-18, Sharma teaches mice were challenged with B16/F10 cells (reading on melanoma) (see Fig. 4; and page 10460, col. 2, para. 2).
Regarding claims 20 and 54, Bartlett discloses a their TLR2 inhibitor being administered with a pharmaceutically acceptable diluent, carrier, or excipient (Bartlett’s claims 3-4) and intraperitoneal administration of their compounds (page 86, line 11); and Sharma discloses intraperitoneal administration of the anti-CTL4. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the TLR2 inhibitor, the CTLA-4 inhibitor, and an acceptable carrier, diluent, or excipient. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Sharma’s teachings of the benefits of co-administration of immunomodulators.
Regarding claims 47-48, Jackson discloses their dosage regimens are adjusted to suit the situation, for example, several doses may be provided daily or weekly, or at other appropriate intervals (page 19, para. 1, last 3 lines).
Regarding the instantly claimed administration rates of once a day or once weekly, Applicant is advised that the courts have stated where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Regarding claim 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
Regarding claim 59, it is noted that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP 2103 I.C. and MPEP § 2111.04.
It is also noted that a “wherein” clause, such as that in claim 59, must give “meaning and purpose to the manipulative steps.” See, MPEP § 2111.04.
Further regarding claim 59, Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Regarding claim 60, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application that co-administration of Bartlett’s TLR2 inhibitor INNA-011 with a CTLA-4 antibody would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Sharma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and; and Sharma’s teaching that a TLR1/2 inhibitor plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Bartlett (WO 2018/176,099 – cited in IDS – previously cited) (“Bartlett”); in view of Jackson (WO 2012/037,612 – cited in IDS – previously cited) (“Jackson”); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”); as applied to claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61; further in view of Nair et al. (Frontiers in Immunology, 2017,8, Article 1178, 18 pages – previously cited) (“Nair”).
The teachings of Bartlett, Jackson, and Sharma are disclosed above and incorporated herein.
Jackson discloses administration of PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells (page 26, para. 2 and Fig. 7).
Sharma teaches TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses (page 10545, col. 1, last para.).
While Bartlett in view of Jackson, further in view of Sharma does not specifically teach wherein treatment reduces or prevents metastasis to the lung; the teachings of Nair are relied upon for these disclosures.
Nair teaches that NK T cells are directly involved in targeting tumor cells (page 3, col. 1, How do NKT Cells Target Tumor Cells;). Nair states that type I NKT cells play a substantial role in providing protection against tumor growth and metastasis (page 6, col. 2, Clinical Trials of NKT Cells).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Bartlett’s TLR2 inhibitors with a CTLA-4 inhibitor, as taught by Jackson in view of Sharma, to reduce or prevent metastasis to the lung. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Jackson’s disclosure that administration of their PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells; Sharma’s teachings that TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses; and Nair’s teachings that an increase in NK T cells play a substantial role in providing protection against tumor growth and metastasis.
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, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 12,195,557 B2 (US ‘557); in view of Bartlett (WO 2018/176,099 – cited in IDS); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61, US ‘557 claims the instant compound of claim 1 (US ‘557’s claims 1 and 5).
While US ‘557 does not claim: (i) a method of treating, preventing, or minimizing progression of cancer in a subject comprising administering to the subject a therapeutically effective amount of their compound and an immunostimulant comprising a CTL-4 antibody (all instant claims); (ii) identifying a subject having cancer (claim 5); (iii) wherein the cancer is metastatic (claim 8); (iv) identifying a subject having a tumor capable of metastasizing; (v) wherein the cancer is breast cancer (claims 17-18); (vi) a pharmaceutical composition comprising an acceptable carrier, diluent, or excipient, and the immunostimulant (claims 19-20 and 54); (vii) administration once daily or weekly (claims 47-48); (vii) intravenous administration (claim 49); or (viii) a kit comprising their compound (claim 61); the teachings of Bartlett, Jackson, and Sharma are relied upon for these disclosures.
Bartlett discloses the compound INNA-011 below (page 50, line 5);
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in page 85 (entry 5). Bartlett teaches their compounds as TLR2 agonists (page 2-3). Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery (page 7, lines 10-12). Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
Jackson’s invention is predicated on the observation that a TLR2 agonist such as Pam2Cys demonstrates the ability to raise an innate immune response in a subject (page 8, lines 20-22). Jackson discloses the TLR2 moiety comprises Pam2Cys conjugated to polyethylene glycol chain (PEG) (page 13, lines 14-15) and contemplates the use of a TLR2 moiety for treating cancer in a subject. Jackson provides a method for treating or preventing cancer by raising an innate immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a TLR2 moiety in solution. In some embodiments, administration of the TLR2 moiety inhibits the growth or spread of cancer (metastasis) (page 17, lines 19-27). The invention claims a method for treating a cancer, which can be caused by an infectious agent, including HPV, HCV, or Epstein Barr Virus (claims 15 and 16). Jackson also provides a pharmaceutical composition comprising an effective amount of a TLR2 moiety in solution together with a pharmaceutically acceptable carrier or excipient for treating or preventing a disease by raising an innate immune response in a subject (page 20, lines 15-17). Jackson’s compositions may be administered by any means known to those skilled in the art, including, but not limited to, intranasally, orally, and intravenously (page 20, lines 22-24). Jackson further discloses their compositions may include other physiologically active agents (page 20, lines 14-15).
Sharma teaches anti-CTLA-4 are widely accepted therapeutic options for many cancers (abstract). Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer US ‘557’s compound, taught by Bartlett’s to be a TLR2 inhibitor, for the treatment of cancer in a subject, in view of Jackson, in combination with an immunostimulant comprising an anti-CTLA-4 antibody, in view of Sharma. One of ordinary skill would have been motivated to do so in view of US ‘557 and Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) and pharmaceutical compositions thereof as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and Sharma’s teaching that Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone. One of ordinary skill would have had a reasonable expectation of success in doing so in view of Jackson’s disclosure that their compositions comprising related TLR2 inhibitors may be administered with other active agents (reading on instantly claimed co-administration of CTLA-4 inhibitors); and Sharma’s teachings.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two agents.
Regarding claim 5, Jackson teaches a method of treatment of cancer. It flows from the art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding claim 7, Jackson teaches the use of a TLR2 moiety as defined herein for treating cancer in a subject; a method for treating or preventing cancer by raising an innate immune response in a subject comprising administering a composition comprising a TLR2 moiety in solution; and a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 8, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 10, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist. It flows from this art that identification of a subject who has a tumor capable of spreading (metastasizing) would occur prior to administration of any treatment of cancer.
Regarding claim 16, Barlett and Jackson in view of Sharma disclose the benefits of co-administering a CTLA-4 antibody with a TLR2 agonist, such as the instant compound.
Regarding claims 17-18, Sharma teaches mice were challenged with B16/F10 cells (reading on melanoma) (see Fig. 4; and page 10460, col. 2, para. 2).
Regarding claims 20 and 54, Bartlett discloses a their TLR2 inhibitor being administered with a pharmaceutically acceptable diluent, carrier, or excipient (Bartlett’s claims 3-4) and intraperitoneal administration of their compounds (page 86, line 11); and Sharma discloses intraperitoneal administration of the anti-CTL4. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the TLR2 inhibitor, the CTLA-4 inhibitor, and an acceptable carrier, diluent, or excipient. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Sharma’s teachings of the benefits of co-administration of immunomodulators.
Regarding claims 47-48, Jackson discloses their dosage regimens are adjusted to suit the situation, for example, several doses may be provided daily or weekly, or at other appropriate intervals (page 19, para. 1, last 3 lines).
Regarding the instantly claimed administration rates of once a day or once weekly, Applicant is advised that the courts have stated where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Regarding claim 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
Regarding claim 59, it is noted that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP 2103 I.C. and MPEP § 2111.04.
It is also noted that a “wherein” clause, such as that in claim 59, must give “meaning and purpose to the manipulative steps.” See, MPEP § 2111.04.
Further regarding claim 59, Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Regarding claim 60, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application that co-administration US ‘557’s compound, taught by Bartlett to be a TLR2 inhibitor, with a CTLA-4 antibody would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Sharma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and; and Sharma’s teaching that a TLR1/2 inhibitor plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone.
Regarding claim 61, Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 12,195,557 B2 (US ‘557); in view of Bartlett (WO 2018/176,099 – cited in IDS); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”); as applied to claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61; further in view of Nair et al. (Frontiers in Immunology, 2017,8, Article 1178, 18 pages).
The teachings of US ‘557, Bartlett, Jackson, and Sharma are disclosed above and incorporated herein.
Jackson further discloses administration of PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells (page 26, para. 2 and Fig. 7).
Sharma teaches TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses (page 10545, col. 1, last para.).
While US ‘557 in view of Bartlett, Jackson, and Sharma does not specifically teach wherein treatment minimizes, reduces, or prevents metastasis to the lung; the teachings of Nair are relied upon for these disclosures.
Nair teaches that NK T cells are directly involved in targeting tumor cells (page 3, col. 1, How do NKT Cells Target Tumor Cells;). Nair states that type I NKT cells play a substantial role in providing protection against tumor growth and metastasis (page 6, col. 2, Clinical Trials of NKT Cells).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer US ‘557’s compound, taught by Bartlett’s to be a TLR2 inhibitor, with a CTLA-4 inhibitor, as taught by Jackson in view of Sharma, to reduce or prevent metastasis to the lung. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Jackson’s disclosure that administration of their PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells; Sharma’s teachings that TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses; and Nair’s teachings that an increase in NK T cells play a substantial role in providing protection against tumor growth and metastasis.
Claims 1, 5, 7-9, 10, 16-20, 47-49, 54, and 59-61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 11, 13-14, 22-23, 25, 27, 29, 31-32, 35, and 53-60 of copending Application No. 17/640,714 (Copending ‘714); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5, 7-9, 10, 16-20, 47-49, 54, and 59-61, Copending ‘714 claims a method of treating, preventing, or minimizing progression of a cancer in a subject comprising administering a therapeutically effective amount of a compound A-Y-B including the compound below, which anticipates the instant compound (Copending ‘714’s claims 1 and 18).
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Regarding claim 5, Copending ‘714 claims their method further comprising identifying a subject with cancer (Copending ‘714’s claim 53).
Regarding instant claim 9, Copending ‘714 claims a method of inhibiting metastasis to the lung (Copending ‘714’s claims 54-55).
Regarding claims 17-18, Copending ‘714 claims a method for the instantly claimed cancers (Copending ‘714’s claim 56).
Regarding instant claim 19, Copending ‘714 claims administration of a pharmaceutical composition comprising their compounds and an acceptable carrier, diluent, or excipient (Copending ‘714’s claim 57).
Regarding instant claim 49, Copending ‘714 claims intravenous administration (Copending ‘714’s claim 58).
Regarding claim 61, Copending ‘714 claims a kit comprising their compounds and instructions for use (Copending ‘714’s claim 60).
While Copending ‘714 does not claim: (i) co-administration of a therapeutically effective amount of their compound and an immunostimulant comprising a CTL-4 antibody (all instant claims); or (ii) administration once daily or weekly (claims 47-48); the teachings of Jackson and Sharma are relied upon for these disclosures.
Jackson discloses TLR2 moiety comprises Pam2Cys conjugated to polyethylene glycol chain (PEG) (page 13, lines 14-15). Jackson contemplates the use of a TLR2 moiety as defined herein for treating cancer in a subject (page 17, lines 19-27). Jackson further discloses their compositions may include other physiologically active agents (page 20, lines 14-15).
Sharma teaches anti-CTLA-4 are widely accepted therapeutic options for many cancers (abstract). Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to co-administer Copending ‘714’s compounds with an immunostimulant comprising CTL-4 antibody, as taught by Jackson in view of Sharma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of US ‘557’s disclosure of their compounds for the treatment of cancers and metastatic cancers; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and Sharma’s teaching that Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two agents.
Regarding instant claim 16, Sharma discloses the benefits of co-administering a CTLA-4 inhibitor with a TLR2 agonist, such as the instant compounds.
Regarding instant claims 47-48, Jackson discloses their dosage regimens are adjusted to suit the situation, for example, several doses may be provided daily or weekly, or at other appropriate intervals (page 19, para. 1, last 3 lines).
Regarding the instantly claimed administration rates of once a day or once weekly, Applicant is reminded that the courts have stated where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Regarding claim 59, Applicant is reminded that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim.
It is also noted that a “wherein” clause, such as that in claim 59, must give “meaning and purpose to the manipulative steps.”
Further regarding claim 59, Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Regarding claim 60, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application that co-administration of Copending ‘451’s compound, taught by Bartlett to be a TLR2 inhibitor, with a CTLA-4 antibody would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Sharma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and; and Sharma’s teaching that a TLR1/2 inhibitor plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 7-9, 10, 16-20, 47-49, 54, and 59-61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-16, 19, 23-26, 29-30, 32, and 52 copending Application No. 17/622,451 (Copending ‘451) – Notice of Allowance Mailed 04/17/2026; in view of Bartlett (WO 2018/176,099 – cited in IDS); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61, Copending ‘451 claims the compound below, reading on the instant compound of claim 1 (Copending ‘451’s claims 1 and 23).
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While Copending ‘451 does not claim: (i) a method of treating, preventing, or minimizing progression of cancer in a subject comprising administering to the subject a therapeutically effective amount of their compound and an immunostimulant comprising a CTLA-4 antibody (all instant claims); (ii) identifying a subject having cancer (claim 5); (iii) wherein the cancer is metastatic (claim 8); (iv) identifying a subject having a tumor capable of metastasizing; (v) wherein the cancer is breast cancer (claims 17-18); (vi) a pharmaceutical composition comprising an acceptable carrier, diluent, or excipient, and the immunostimulant (claims 19-20 and 54); (vii) administration once daily or weekly (claims 47-48); (vii) intravenous administration (claim 49); or (viii) a kit comprising their compound (claim 61); the teachings of Bartlett, Jackson, and Sharma are relied upon for these disclosures.
Bartlett discloses the compound INNA-011 below (page 50, line 5);
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in page 85 (entry 5). Bartlett teaches their compounds as TLR2 agonists (page 2-3). Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery (page 7, lines 10-12). Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
Jackson’s invention is predicated on the observation that a TLR2 agonist such as Pam2Cys demonstrates the ability to raise an innate immune response in a subject (page 8, lines 20-22). Jackson discloses the TLR2 moiety comprises Pam2Cys conjugated to polyethylene glycol chain (PEG) (page 13, lines 14-15) and contemplates the use of a TLR2 moiety for treating cancer in a subject. Jackson provides a method for treating or preventing cancer by raising an innate immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a TLR2 moiety in solution. In some embodiments, administration of the TLR2 moiety inhibits the growth or spread of cancer (metastasis) (page 17, lines 19-27). The invention claims a method for treating a cancer, which can be caused by an infectious agent, including HPV, HCV, or Epstein Barr Virus (claims 15 and 16). Jackson also provides a pharmaceutical composition comprising an effective amount of a TLR2 moiety in solution together with a pharmaceutically acceptable carrier or excipient for treating or preventing a disease by raising an innate immune response in a subject (page 20, lines 15-17). Jackson’s compositions may be administered by any means known to those skilled in the art, including, but not limited to, intranasally, orally, and intravenously (page 20, lines 22-24). Jackson further discloses their compositions may include other physiologically active agents (page 20, lines 14-15).
Sharma teaches anti-CTLA-4 are widely accepted therapeutic options for many cancers (abstract). Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Copending ‘451’s compound, taught by Bartlett’s to be a TLR2 inhibitor, for the treatment of cancer in a subject, in view of Jackson, in combination with an immunostimulant comprising an anti-CTLA-4 antibody, in view of Sharma. One of ordinary skill would have been motivated to do so in view of Copending ‘451 and Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) and pharmaceutical compositions thereof as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and Sharma’s teaching that Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone. One of ordinary skill would have had a reasonable expectation of success in doing so in view of Jackson’s disclosure that their compositions comprising related TLR2 inhibitors may be administered with other active agents (reading on instantly claimed co-administration of CTLA-4 inhibitors); and Sharma’s teachings.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two agents.
Regarding claim 5, Jackson teaches a method of treatment of cancer. It flows from the art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding claim 7, Jackson teaches the use of a TLR2 moiety as defined herein for treating cancer in a subject; a method for treating or preventing cancer by raising an innate immune response in a subject comprising administering a composition comprising a TLR2 moiety in solution; and a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 8, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 10, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist. It flows from this art that identification of a subject who has a tumor capable of spreading (metastasizing) would occur prior to administration of any treatment of cancer.
Regarding claim 16, Barlett and Jackson in view of Sharma disclose the benefits of co-administering a CTLA-4 antibody with a TLR2 agonist, such as the instant compound.
Regarding claims 17-18, Sharma teaches mice were challenged with B16/F10 cells (reading on melanoma) (see Fig. 4; and page 10460, col. 2, para. 2).
Regarding claims 20 and 54, Bartlett discloses a their TLR2 inhibitor being administered with a pharmaceutically acceptable diluent, carrier, or excipient (Bartlett’s claims 3-4) and intraperitoneal administration of their compounds (page 86, line 11); and Sharma discloses intraperitoneal administration of the anti-CTL4. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the TLR2 inhibitor, the CTLA-4 inhibitor, and an acceptable carrier, diluent, or excipient. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Sharma’s teachings of the benefits of co-administration of immunomodulators.
Regarding claims 47-48, Jackson discloses their dosage regimens are adjusted to suit the situation, for example, several doses may be provided daily or weekly, or at other appropriate intervals (page 19, para. 1, last 3 lines).
Regarding the instantly claimed administration rates of once a day or once weekly, Applicant is advised that the courts have stated where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Regarding claim 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
Regarding claim 59, it is noted that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP 2103 I.C. and MPEP § 2111.04.
It is also noted that a “wherein” clause, such as that in claim 59, must give “meaning and purpose to the manipulative steps.” See, MPEP § 2111.04.
Further regarding claim 59, Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Regarding claim 60, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application that co-administration of Copending ‘451’s compound, taught by Bartlett to be a TLR2 inhibitor, with a CTLA-4 antibody, would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Sharma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and; and Sharma’s teaching that a TLR1/2 inhibitor plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone.
Regarding claim 61, Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-16, 19, 23-26, 29-30, 32, and 52 copending Application No. 17/622,451 (Copending ‘451); in view of Bartlett (WO 2018/176,099 – cited in IDS); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”); as applied to claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61; further in view of Nair et al. (Frontiers in Immunology, 2017,8, Article 1178, 18 pages).
The teachings of Copending ‘451, Bartlett, Jackson, and Sharma are disclosed above and incorporated herein.
Jackson further discloses administration of PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells (page 26, para. 2 and Fig. 7).
Sharma teaches TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses (page 10545, col. 1, last para.).
While Copending ‘451 in view of Bartlett, Jackson, and Sharma does not specifically teach wherein treatment minimizes, reduces, or prevents metastasis to the lung; the teachings of Nair are relied upon for these disclosures.
Nair teaches that NK T cells are directly involved in targeting tumor cells (page 3, col. 1, How do NKT Cells Target Tumor Cells;). Nair states that type I NKT cells play a substantial role in providing protection against tumor growth and metastasis (page 6, col. 2, Clinical Trials of NKT Cells).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Copending ‘451’s compound, taught by Bartlett’s to be a TLR2 inhibitor, with a CTLA-4 inhibitor, as taught by Jackson in view of Sharma, to reduce or prevent metastasis to the lung. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Jackson’s disclosure that administration of their PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells; Sharma’s teachings that TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses; and Nair’s teachings that an increase in NK T cells play a substantial role in providing protection against tumor growth and metastasis.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 7-9, 10, 16-20, 47-49, 54, and 59-61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 8, 10-12, 15-23, and 43 of Copending Application No. 17/926,886 (Copending ‘886); in view of Bartlett (WO 2018/176,099 – cited in IDS); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61, Copending ‘886 claims a method of treating or reducing a coronavirus infection comprising administration of a compound of Formula A-Y-B, including the TLR2 inhibitor compound of instant claim 1 (A108) (Copending ‘886’s claims 1-3 and 23).
While Copending ‘886 does not claim: (i) a method of treating, preventing, or minimizing progression of cancer in a subject comprising administering to the subject a therapeutically effective amount of their compound and an immunostimulant comprising a CTLA-4 antibody (all instant claims); (ii) identifying a subject having cancer (claim 5); (iii) wherein the cancer is metastatic (claim 8); (iv) identifying a subject having a tumor capable of metastasizing; (v) wherein the cancer is breast cancer (claims 17-18); (vi) a pharmaceutical composition comprising an acceptable carrier, diluent, or excipient, and the immunostimulant (claims 19-20 and 54); (vii) administration once daily or weekly (claims 47-48); (vii) intravenous administration (claim 49); or (viii) a kit comprising their compound (claim 61); the teachings of Bartlett, Jackson, and Sharma are relied upon for these disclosures.
Bartlett discloses the compound INNA-011 below (page 50, line 5);
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in page 85 (entry 5). Bartlett teaches their compounds as TLR2 agonists (page 2-3). Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery (page 7, lines 10-12). Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
Jackson’s invention is predicated on the observation that a TLR2 agonist such as Pam2Cys demonstrates the ability to raise an innate immune response in a subject (page 8, lines 20-22). Jackson discloses the TLR2 moiety comprises Pam2Cys conjugated to polyethylene glycol chain (PEG) (page 13, lines 14-15) and contemplates the use of a TLR2 moiety for treating cancer in a subject. Jackson provides a method for treating or preventing cancer by raising an innate immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a TLR2 moiety in solution. In some embodiments, administration of the TLR2 moiety inhibits the growth or spread of cancer (metastasis) (page 17, lines 19-27). The invention claims a method for treating a cancer, which can be caused by an infectious agent, including HPV, HCV, or Epstein Barr Virus (claims 15 and 16). Jackson also provides a pharmaceutical composition comprising an effective amount of a TLR2 moiety in solution together with a pharmaceutically acceptable carrier or excipient for treating or preventing a disease by raising an innate immune response in a subject (page 20, lines 15-17). Jackson’s compositions may be administered by any means known to those skilled in the art, including, but not limited to, intranasally, orally, and intravenously (page 20, lines 22-24). Jackson further discloses their compositions may include other physiologically active agents (page 20, lines 14-15).
Sharma teaches anti-CTLA-4 are widely accepted therapeutic options for many cancers (abstract). Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Copending ‘886’s compound, taught by Bartlett’s to be a TLR2 inhibitor, for the treatment of cancer in a subject, in view of Jackson, in combination with an immunostimulant comprising an anti-CTLA-4 antibody, in view of Sharma. One of ordinary skill would have been motivated to do so in view of Copending ‘886 and Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) and pharmaceutical compositions thereof as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and Sharma’s teaching that Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone. One of ordinary skill would have had a reasonable expectation of success in doing so in view of Jackson’s disclosure that their compositions comprising related TLR2 inhibitors may be administered with other active agents (reading on instantly claimed co-administration of CTLA-4 inhibitors); and Sharma’s teachings.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two agents.
Regarding claim 5, Jackson teaches a method of treatment of cancer. It flows from the art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding claim 7, Jackson teaches the use of a TLR2 moiety as defined herein for treating cancer in a subject; a method for treating or preventing cancer by raising an innate immune response in a subject comprising administering a composition comprising a TLR2 moiety in solution; and a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 8, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 10, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist. It flows from this art that identification of a subject who has a tumor capable of spreading (metastasizing) would occur prior to administration of any treatment of cancer.
Regarding claim 16, Barlett and Jackson in view of Sharma disclose the benefits of co-administering a CTLA-4 antibody with a TLR2 agonist, such as the instant compound.
Regarding claims 17-18, Sharma teaches mice were challenged with B16/F10 cells (reading on melanoma) (see Fig. 4; and page 10460, col. 2, para. 2).
Regarding claims 20 and 54, Bartlett discloses a their TLR2 inhibitor being administered with a pharmaceutically acceptable diluent, carrier, or excipient (Bartlett’s claims 3-4) and intraperitoneal administration of their compounds (page 86, line 11); and Sharma discloses intraperitoneal administration of the anti-CTL4. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the TLR2 inhibitor, the CTLA-4 inhibitor, and an acceptable carrier, diluent, or excipient. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Sharma’s teachings of the benefits of co-administration of immunomodulators.
Regarding claims 47-48, Jackson discloses their dosage regimens are adjusted to suit the situation, for example, several doses may be provided daily or weekly, or at other appropriate intervals (page 19, para. 1, last 3 lines).
Regarding the instantly claimed administration rates of once a day or once weekly, Applicant is advised that the courts have stated where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Regarding claim 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
Regarding claim 59, it is noted that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP 2103 I.C. and MPEP § 2111.04.
It is also noted that a “wherein” clause, such as that in claim 59, must give “meaning and purpose to the manipulative steps.” See, MPEP § 2111.04.
Further regarding claim 59, Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Regarding claim 60, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application that co-administration of Copending ‘886’s compound, taught by Bartlett to be a TLR2 inhibitor, with a CTLA-4 antibody, would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Sharma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and; and Sharma’s teaching that a TLR1/2 inhibitor plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone.
Regarding claim 61, Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 8, 10-12, 15-23, and 43 of Copending Application No. 17/926,886 (Copending ‘886); in view of Bartlett (WO 2018/176,099 – cited in IDS); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”); as applied to claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61; further in view of Nair et al. (Frontiers in Immunology, 2017,8, Article 1178, 18 pages).
The teachings of Copending ‘886, Bartlett, Jackson, and Sharma are disclosed above and incorporated herein.
Jackson further discloses administration of PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells (page 26, para. 2 and Fig. 7).
Sharma teaches TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses (page 10545, col. 1, last para.).
While Copending ‘886 in view of Bartlett, Jackson, and Sharma does not specifically teach wherein treatment minimizes, reduces, or prevents metastasis to the lung; the teachings of Nair are relied upon for these disclosures.
Nair teaches that NK T cells are directly involved in targeting tumor cells (page 3, col. 1, How do NKT Cells Target Tumor Cells;). Nair states that type I NKT cells play a substantial role in providing protection against tumor growth and metastasis (page 6, col. 2, Clinical Trials of NKT Cells).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Copending ‘886’s compound, taught by Bartlett’s to be a TLR2 inhibitor, with a CTLA-4 inhibitor, as taught by Jackson in view of Sharma, to reduce or prevent metastasis to the lung. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Jackson’s disclosure that administration of their PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells; Sharma’s teachings that TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses; and Nair’s teachings that an increase in NK T cells play a substantial role in providing protection against tumor growth and metastasis.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 7-9, 10, 16-20, 47-49, 54, and 59-61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 79 of Copending Application No. 16/768,278 (Copending ‘278); in view of Bartlett (WO 2018/176,099 – cited in IDS); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61, Copending ‘278 claims a method of treating or preventing a respiratory infection comprising administration of a TLR2 inhibitor compound of instant claim 1 (A108) (Copending ‘278’s claims 1 and 79).
While Copending ‘278 does not claim: (i) a method of treating, preventing, or minimizing progression of cancer in a subject comprising administering to the subject a therapeutically effective amount of their compound and an immunostimulant comprising a CTLA-4 antibody (all instant claims); (ii) identifying a subject having cancer (claim 5); (iii) wherein the cancer is metastatic (claim 8); (iv) identifying a subject having a tumor capable of metastasizing; (v) wherein the cancer is breast cancer (claims 17-18); (vi) a pharmaceutical composition comprising an acceptable carrier, diluent, or excipient, and the immunostimulant (claims 19-20 and 54); (vii) administration once daily or weekly (claims 47-48); (vii) intravenous administration (claim 49); or (viii) a kit comprising their compound (claim 61); the teachings of Bartlett, Jackson, and Sharma are relied upon for these disclosures.
Bartlett discloses the compound INNA-011 below (page 50, line 5);
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in page 85 (entry 5). Bartlett teaches their compounds as TLR2 agonists (page 2-3). Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery (page 7, lines 10-12). Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
Jackson’s invention is predicated on the observation that a TLR2 agonist such as Pam2Cys demonstrates the ability to raise an innate immune response in a subject (page 8, lines 20-22). Jackson discloses the TLR2 moiety comprises Pam2Cys conjugated to polyethylene glycol chain (PEG) (page 13, lines 14-15) and contemplates the use of a TLR2 moiety for treating cancer in a subject. Jackson provides a method for treating or preventing cancer by raising an innate immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a TLR2 moiety in solution. In some embodiments, administration of the TLR2 moiety inhibits the growth or spread of cancer (metastasis) (page 17, lines 19-27). The invention claims a method for treating a cancer, which can be caused by an infectious agent, including HPV, HCV, or Epstein Barr Virus (claims 15 and 16). Jackson also provides a pharmaceutical composition comprising an effective amount of a TLR2 moiety in solution together with a pharmaceutically acceptable carrier or excipient for treating or preventing a disease by raising an innate immune response in a subject (page 20, lines 15-17). Jackson’s compositions may be administered by any means known to those skilled in the art, including, but not limited to, intranasally, orally, and intravenously (page 20, lines 22-24). Jackson further discloses their compositions may include other physiologically active agents (page 20, lines 14-15).
Sharma teaches anti-CTLA-4 are widely accepted therapeutic options for many cancers (abstract). Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Copending ‘278’s compound, taught by Bartlett’s to be a TLR2 inhibitor, for the treatment of cancer in a subject, in view of Jackson, in combination with an immunostimulant comprising an anti-CTLA-4 antibody, in view of Sharma. One of ordinary skill would have been motivated to do so in view of Copending ‘278 and Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) and pharmaceutical compositions thereof as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and Sharma’s teaching that Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone. One of ordinary skill would have had a reasonable expectation of success in doing so in view of Jackson’s disclosure that their compositions comprising related TLR2 inhibitors may be administered with other active agents (reading on instantly claimed co-administration of CTLA-4 inhibitors); and Sharma’s teachings.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two agents.
Regarding claim 5, Jackson teaches a method of treatment of cancer. It flows from the art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding claim 7, Jackson teaches the use of a TLR2 moiety as defined herein for treating cancer in a subject; a method for treating or preventing cancer by raising an innate immune response in a subject comprising administering a composition comprising a TLR2 moiety in solution; and a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 8, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 10, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist. It flows from this art that identification of a subject who has a tumor capable of spreading (metastasizing) would occur prior to administration of any treatment of cancer.
Regarding claim 16, Barlett and Jackson in view of Sharma disclose the benefits of co-administering a CTLA-4 antibody with a TLR2 agonist, such as the instant compound.
Regarding claims 17-18, Sharma teaches mice were challenged with B16/F10 cells (reading on melanoma) (see Fig. 4; and page 10460, col. 2, para. 2).
Regarding claims 20 and 54, Bartlett discloses a their TLR2 inhibitor being administered with a pharmaceutically acceptable diluent, carrier, or excipient (Bartlett’s claims 3-4) and intraperitoneal administration of their compounds (page 86, line 11); and Sharma discloses intraperitoneal administration of the anti-CTL4. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the TLR2 inhibitor, the CTLA-4 inhibitor, and an acceptable carrier, diluent, or excipient. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Sharma’s teachings of the benefits of co-administration of immunomodulators.
Regarding claims 47-48, Jackson discloses their dosage regimens are adjusted to suit the situation, for example, several doses may be provided daily or weekly, or at other appropriate intervals (page 19, para. 1, last 3 lines).
Regarding the instantly claimed administration rates of once a day or once weekly, Applicant is advised that the courts have stated where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Regarding claim 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
Regarding claim 59, it is noted that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP 2103 I.C. and MPEP § 2111.04.
It is also noted that a “wherein” clause, such as that in claim 59, must give “meaning and purpose to the manipulative steps.” See, MPEP § 2111.04.
Further regarding claim 59, Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Regarding claim 60, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application that co-administration of Copending ‘278’s compound, taught by Bartlett to be a TLR2 inhibitor, with a CTLA-4 antibody, would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Sharma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and; and Sharma’s teaching that a TLR1/2 inhibitor plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone.
Regarding claim 61, Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 79 of Copending Application No. 16/268,278 (Copending ‘278); in view of Bartlett (WO 2018/176,099 – cited in IDS); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”); as applied to claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61; further in view of Nair et al. (Frontiers in Immunology, 2017,8, Article 1178, 18 pages).
The teachings of Copending ‘278, Bartlett, Jackson, and Sharma are disclosed above and incorporated herein.
Jackson further discloses administration of PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells (page 26, para. 2 and Fig. 7).
Sharma teaches TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses (page 10545, col. 1, last para.).
While Copending ‘278 in view of Bartlett, Jackson, and Sharma does not specifically teach wherein treatment minimizes, reduces, or prevents metastasis to the lung; the teachings of Nair are relied upon for these disclosures.
Nair teaches that NK T cells are directly involved in targeting tumor cells (page 3, col. 1, How do NKT Cells Target Tumor Cells;). Nair states that type I NKT cells play a substantial role in providing protection against tumor growth and metastasis (page 6, col. 2, Clinical Trials of NKT Cells).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Copending ‘278’s compound, taught by Bartlett’s to be a TLR2 inhibitor, with a CTLA-4 inhibitor, as taught by Jackson in view of Sharma, to reduce or prevent metastasis to the lung. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Jackson’s disclosure that administration of their PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells; Sharma’s teachings that TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses; and Nair’s teachings that an increase in NK T cells play a substantial role in providing protection against tumor growth and metastasis.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 5, 7-9, 10, 16-20, 47-49, 54, and 59-61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, and 19-20 of Copending Application No. 18/931,434 (Copending ‘434); in view of Bartlett (WO 2018/176,099 – cited in IDS); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61, Copending ‘434 claims the instant compound of claim 1, and a method of raising an immune response comprising administration of the instant compound of claim 1 (Copending ‘434’s claims 1, 17, and 19-20).
While Copending ‘434 does not claim: (i) a method of treating, preventing, or minimizing progression of cancer in a subject comprising administering to the subject a therapeutically effective amount of their compound and an immunostimulant comprising a CTLA-4 antibody (all instant claims); (ii) identifying a subject having cancer (claim 5); (iii) wherein the cancer is metastatic (claim 8); (iv) identifying a subject having a tumor capable of metastasizing; (v) wherein the cancer is breast cancer (claims 17-18); (vi) a pharmaceutical composition comprising an acceptable carrier, diluent, or excipient, and the immunostimulant (claims 19-20 and 54); (vii) administration once daily or weekly (claims 47-48); (vii) intravenous administration (claim 49); or (viii) a kit comprising their compound (claim 61); the teachings of Bartlett, Jackson, and Sharma are relied upon for these disclosures.
Bartlett discloses the compound INNA-011 below (page 50, line 5);
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in page 85 (entry 5). Bartlett teaches their compounds as TLR2 agonists (page 2-3). Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery (page 7, lines 10-12). Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
Jackson’s invention is predicated on the observation that a TLR2 agonist such as Pam2Cys demonstrates the ability to raise an innate immune response in a subject (page 8, lines 20-22). Jackson discloses the TLR2 moiety comprises Pam2Cys conjugated to polyethylene glycol chain (PEG) (page 13, lines 14-15) and contemplates the use of a TLR2 moiety for treating cancer in a subject. Jackson provides a method for treating or preventing cancer by raising an innate immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a TLR2 moiety in solution. In some embodiments, administration of the TLR2 moiety inhibits the growth or spread of cancer (metastasis) (page 17, lines 19-27). The invention claims a method for treating a cancer, which can be caused by an infectious agent, including HPV, HCV, or Epstein Barr Virus (claims 15 and 16). Jackson also provides a pharmaceutical composition comprising an effective amount of a TLR2 moiety in solution together with a pharmaceutically acceptable carrier or excipient for treating or preventing a disease by raising an innate immune response in a subject (page 20, lines 15-17). Jackson’s compositions may be administered by any means known to those skilled in the art, including, but not limited to, intranasally, orally, and intravenously (page 20, lines 22-24). Jackson further discloses their compositions may include other physiologically active agents (page 20, lines 14-15).
Sharma teaches anti-CTLA-4 are widely accepted therapeutic options for many cancers (abstract). Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Copending ‘434’s compound, taught by Bartlett’s to be a TLR2 inhibitor, for the treatment of cancer in a subject, in view of Jackson, in combination with an immunostimulant comprising an anti-CTLA-4 antibody, in view of Sharma. One of ordinary skill would have been motivated to do so in view of Copending ‘434 and Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) and pharmaceutical compositions thereof as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and Sharma’s teaching that Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone. One of ordinary skill would have had a reasonable expectation of success in doing so in view of Jackson’s disclosure that their compositions comprising related TLR2 inhibitors may be administered with other active agents (reading on instantly claimed co-administration of CTLA-4 inhibitors); and Sharma’s teachings.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two agents.
Regarding claim 5, Jackson teaches a method of treatment of cancer. It flows from the art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding claim 7, Jackson teaches the use of a TLR2 moiety as defined herein for treating cancer in a subject; a method for treating or preventing cancer by raising an innate immune response in a subject comprising administering a composition comprising a TLR2 moiety in solution; and a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 8, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist (page 17, lines 19-27).
Regarding claim 10, Jackson teaches a method of inhibiting the growth or spread of cancer (reading on metastasis) by administering a composition comprising a TLR2 agonist. It flows from this art that identification of a subject who has a tumor capable of spreading (metastasizing) would occur prior to administration of any treatment of cancer.
Regarding claim 16, Barlett and Jackson in view of Sharma disclose the benefits of co-administering a CTLA-4 antibody with a TLR2 agonist, such as the instant compound.
Regarding claims 17-18, Sharma teaches mice were challenged with B16/F10 cells (reading on melanoma) (see Fig. 4; and page 10460, col. 2, para. 2).
Regarding claims 20 and 54, Bartlett discloses a their TLR2 inhibitor being administered with a pharmaceutically acceptable diluent, carrier, or excipient (Bartlett’s claims 3-4) and intraperitoneal administration of their compounds (page 86, line 11); and Sharma discloses intraperitoneal administration of the anti-CTL4. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the TLR2 inhibitor, the CTLA-4 inhibitor, and an acceptable carrier, diluent, or excipient. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Sharma’s teachings of the benefits of co-administration of immunomodulators.
Regarding claims 47-48, Jackson discloses their dosage regimens are adjusted to suit the situation, for example, several doses may be provided daily or weekly, or at other appropriate intervals (page 19, para. 1, last 3 lines).
Regarding the instantly claimed administration rates of once a day or once weekly, Applicant is advised that the courts have stated where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Regarding claim 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
Regarding claim 59, it is noted that the subject matter of a properly construed claim is defined by the terms that limit its scope. It is this subject matter that must be examined. As a general matter, the grammar and intended meaning of terms used in a claim will dictate whether the language limits the claim scope. Language that suggests or makes optional but does not require steps to be performed or does not limit a claim to a particular structure does not limit the scope of a claim or claim limitation. “Wherein” clauses are examples of language that may raise a question as to the limiting effect of the language in a claim. See MPEP 2103 I.C. and MPEP § 2111.04.
It is also noted that a “wherein” clause, such as that in claim 59, must give “meaning and purpose to the manipulative steps.” See, MPEP § 2111.04.
Further regarding claim 59, Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Regarding claim 60, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application that co-administration of Copending ‘434’s compound, taught by Bartlett to be a TLR2 inhibitor, with a CTLA-4 antibody, would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Sharma. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and; and Sharma’s teaching that a TLR1/2 inhibitor plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone.
Regarding claim 61, Bartlett discloses a kit comprising their TLR2 inhibitors, pharmaceutically acceptable salts, diluents, or excipients. Bartlett discloses their kit may comprise instruction for use in any method or use of their invention (page 82, lines 16-21).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 9 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 17, and 19-20 of Copending Application No. 18/931,434 (Copending ‘434); in view of Bartlett (WO 2018/176,099 – cited in IDS); in view of Jackson (WO 2012/037,612 – cited in IDS); further in view of Sharma et al. (Proc. Natl. Acad. Sci. U.S.A. 116 (21) 10453-10462, https://doi.org/10.1073/pnas.1819004116 (2019)) (“Sharma”); as applied to claims 1, 5, 7-8, 10, 16-20, 47-49, 54, and 59-61; further in view of Nair et al. (Frontiers in Immunology, 2017,8, Article 1178, 18 pages).
The teachings of Copending ‘434, Bartlett, Jackson, and Sharma are disclosed above and incorporated herein.
Jackson further discloses administration of PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells (page 26, para. 2 and Fig. 7).
Sharma teaches TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses (page 10545, col. 1, last para.).
While Copending ‘434 in view of Bartlett, Jackson, and Sharma does not specifically teach wherein treatment minimizes, reduces, or prevents metastasis to the lung; the teachings of Nair are relied upon for these disclosures.
Nair teaches that NK T cells are directly involved in targeting tumor cells (page 3, col. 1, How do NKT Cells Target Tumor Cells;). Nair states that type I NKT cells play a substantial role in providing protection against tumor growth and metastasis (page 6, col. 2, Clinical Trials of NKT Cells).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Copending ‘434’s compound, taught by Bartlett’s to be a TLR2 inhibitor, with a CTLA-4 inhibitor, as taught by Jackson in view of Sharma, to reduce or prevent metastasis to the lung. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Jackson’s disclosure that administration of their PEGylated Pam2Cys expands pulmonary cell populations, including NK T cells; Sharma’s teachings that TLR2 is expressed by natural killer (NK) cells and B cells, which have been shown to be activated by TLR2 ligand to produce antitumor and antipathogen responses; and Nair’s teachings that an increase in NK T cells play a substantial role in providing protection against tumor growth and metastasis.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Claims
Claim amendments are acknowledged and have been entered. No new matter has been introduced.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 06/25/2026 have been fully considered but they are not persuasive. Nevertheless, a new ground of rejections is raised herein in view of Bartlett, Jackson, and Sharma.
Applicant cites Fig 9 to say A108 has ‘exquisite activity’ as a TLR2 agonist, in accordance with Bartlett, and states Bartlett is silent about using their compound for treating cancer. Applicant argues Jackson provides no working examples of a TLR2 agonist. Applicant argues rejections presented are not supported by Jackson’s disclosure, since they provide no motivation to combine with a checkpoint inhibitor. Applicant argues the only way examiner could make this combination is through hindsight reasoning.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to Applicant’s reference to Fig. 9, this Figure merely shows the activity of A108 alone, and therefore, the information therein is not commensurate with the scope of the claims.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Sharma teaches anti-CTLA-4 are widely accepted therapeutic options for many cancers (abstract). Sharma specifically teaches Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer Bartlett’s TLR2 inhibitor INNA-011 shown above, for the treatment of cancer in a subject, in view of Jackson, in combination with an immunostimulant comprising an anti-CTLA-4 antibody, in view of Sharma. One of ordinary skill would have been motivated to do so in view of Bartlett’s disclosure of the compound INNA-011 (same as the instant compound of claim 1) and pharmaceutical compositions thereof as a TLR2 inhibitor; Jackson’s teachings that compositions comprising similar TLR2 agonists (such as PEGylated Pam2Cys) may be used for treating and preventing cancer and inhibit metastasis; and Sharma’s teaching that Pam3CSK4 (a TLR1/2 inhibitor) plus anti-CTLA-4 enhanced antitumor immune responses both qualitatively and quantitatively over anti–CTLA-4 alone. One of ordinary skill would have had a reasonable expectation of success in doing so in view of Jackson’s disclosure that their compositions comprising related TLR2 inhibitors may be administered with other active agents (reading on instantly claimed co-administration of CTLA-4 inhibitors); and Sharma’s teachings.
Applicant is reminded that the courts have found that “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art. It is therefore obvious to provide a mixture of the two agents.
Furthermore, Applicant is advised that “[A] prior art reference must be considered in its entirety, i.e., as a whole” W.L. Gore & Associates, Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983) (see MPEP 2141.02 VI). Thus, while the rejections listed above present a modified interpretation of the teachings of the previously cited prior solely for the purpose of clarity, the claims remain rejected over the prior art of record.
Double Patenting
Applicant's arguments filed 01/29/2026 have been fully considered but they are not persuasive.
Applicant argues that none of the copending applications or patents cited require a TLR2 agonist compound in combination with an immunostimulant to treat or prevent cancer. Applicant further states that US ‘886 and ‘278 do not relate to cancer therapy. Applicant further cites the “unexpected results” – however, these results are entirely expected in view of the rejections presented herein, and thus, these arguments are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
