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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/29/2026 was filed after the mailing date of the non-final on 10/01/025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages – previously cited) (“Lu”).
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 PD-1/PD-L1 inhibitor; the teachings of Jackson and Lu 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).
Lu teaches that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists (page 2, col. 3, para. 1, last 4 lines). Lu discloses that TLR ligation not only initiates immune response, but also triggers negative regulatory path- ways; induction of these regulatory pathways represents a major obstacle in developing TLR agonists as cancer immune-therapeutics, and the promise of using TLR agonists to eradicate tumor cells probably won’t be realized unless we block the negative regulators like PD-L1 and tip the balance toward an overwhelming pro-inflammatory (anti-tumor) responses (page 2, col. 3, para. 3; and Figure 1). Lu specifically teaches that cancer immunologists are now exploring novel combinational therapies that combine TLR ligation with blockade of the negative regulators, such as PD-1.
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 PD-1 or PD-L1 antibody, in view of Lu. 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 Lu’s teaching that the promise of using TLR agonists to eradicate tumor cells probably won’t be realized unless we block the negative regulators like PD-L1 and tip the balance toward an overwhelming pro-inflammatory (anti-tumor) responses. 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 PD-1/PD-L1 inhibitors); and Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists, and their disclosure that cancer immunologists are now exploring novel combinational therapies that combine TLR ligation with blockade of the negative regulators, such as PD-1.
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 Lu disclose the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds.
Regarding claim 17, Jackson speaks to a method of treating a cancer caused by Human Papilloma Virus (HPV) (Jackson’s claim 16), reading on vaginal and cervical tumors. Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for treating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding claim 18, Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for treating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding claims 20 and 54, Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery and Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the TLR2 inhibitor, the PD-1/PD-L2 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 Lu’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, Lu discloses that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists. Therefore, it would be obvious from the art that co-administration of a TLR2 agonist with an immunostimulant PD-1/PD-L1 inhibitor would result in an improvement of the effectiveness of a treatment with the immunostimulants alone.
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 PD-1 or PD-L1 antibody would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Lu. 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 Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages – previously cited) (“Lu”); 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 Lu 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).
While Bartlett in view of Jackson, further in view of Lu 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 PD-1/PD-L1 inhibitor, as taught by Jackson in view of Lu, 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; 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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages). 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 PD-1 or PD-L1 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 Lu 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).
Lu teaches that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists (page 2, col. 3, para. 1, last 4 lines).
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 to be a TLR2 inhibitor, for the treatment, prevention, or minimization of progression of cancer in a subject, with an immunostimulant comprising PD-1 or PD-L1 antibody, as taught by Jackson in view of Lu. One of ordinary skill would have been motivated to do so in view of US ‘557’s disclosure of their compound; Bartlett’s disclosure of the compound is 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. 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 PD-1/PD-L1 inhibitors); and Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
Regarding instant claim 5, Jackson teaches a method of treatment of cancer. It flows from this art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding instant 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 instant 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 instant 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 instant claim 16, Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds.
Regarding instant claim 17, Jackson speaks to a method of treating a cancer caused by Human Papilloma Virus (HPV) (Jackson’s claim 16), reading on vaginal and cervical tumors. Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for rerating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding instant claim 18, Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for rerating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding instant claims 20 and 54, Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery and Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the US ‘557’s TLR2 inhibitor, as taught by Bartlett, the PD-1/PD-L2 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 US ‘557’s disclosure of their compound; Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Lu’s teachings of the benefits of co-administration of immunomodulators.
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 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 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
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, Lu discloses that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists. Therefore, it would be obvious from the art that co-administration of a TLR2 agonist with an immunostimulant PD-1/PD-L1 inhibitor would result in an improvement of the effectiveness of a treatment with the immunostimulants alone.
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 US ‘557’s compound, taught by Bartlett to be a TLR2 inhibitor, with a PD-1 or PD-L1 antibody would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Lu. 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 compound; Bartlett’s disclosure that US ‘557’s compound is 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 Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages); 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 Lu 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).
While US ‘557 in view of Bartlett, Jackson, and Lu 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 to be a TLR2 inhibitors, with a PD-1/PD-L1 inhibitor, as taught by Jackson in view of Lu, to minimize, 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; 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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages). 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 PD-1 or PD-L1 antibody (all instant claims); or (ii) administration once daily or weekly (claims 47-48); the teachings of Jackson and Lu 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).
Lu teaches that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists (page 2, col. 3, para. 1, last 4 lines).
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 PD-1 or PD-L1 antibody, as taught by Jackson in view of Lu. 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 Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
Regarding instant claim 16, Lu discloses the benefits of co-administering a PD-1 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, Lu discloses that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists. Therefore, it would be obvious from the art that co-administration of a TLR2 agonist with an immunostimulant PD-1/PD-L1 inhibitor would result in an improvement of the effectiveness of a treatment with the immunostimulants alone.
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 ‘714’s compound with a PD-1 or PD-L1 antibody would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Lu. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘714’s disclosure of their compound; 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 Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
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); 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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages). 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 PD-1 or PD-L1 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 Lu 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).
Lu teaches that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists (page 2, col. 3, para. 1, last 4 lines).
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 to be a TLR2 inhibitor, for the treatment, prevention, or minimization of progression of cancer in a subject, with an immunostimulant comprising PD-1 or PD-L1 antibody, as taught by Jackson in view of Lu. One of ordinary skill would have been motivated to do so in view of Copending ‘451’s disclosure of their compound; Bartlett’s disclosure of the compound is 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. 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 PD-1/PD-L1 inhibitors); and Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
Regarding instant claim 5, Jackson teaches a method of treatment of cancer. It flows from this art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding instant 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 instant 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 instant 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 instant claim 16, Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds.
Regarding instant claim 17, Jackson speaks to a method of treating a cancer caused by Human Papilloma Virus (HPV) (Jackson’s claim 16), reading on vaginal and cervical tumors. Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for rerating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding instant claim 18, Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for rerating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding instant claims 20 and 54, Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery and Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the Copending ‘451’s TLR2 inhibitor, as taught by Bartlett, the PD-1/PD-L2 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 Copending ‘451’s disclosure of their compound; Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Lu’s teachings of the benefits of co-administration of immunomodulators.
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 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 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
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, Lu discloses that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists. Therefore, it would be obvious from the art that co-administration of a TLR2 agonist with an immunostimulant PD-1/PD-L1 inhibitor would result in an improvement of the effectiveness of a treatment with the immunostimulants alone.
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 PD-1 or PD-L1 antibody would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Lu. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘451’s disclosure of their compound; Bartlett’s disclosure that Copending ‘451’s compound is 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 Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages); 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 Lu 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).
While Copending ‘451 in view of Bartlett, Jackson, and Lu et al. 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 to be a TLR2 inhibitors, with a PD-1/PD-L1 inhibitor, as taught by Jackson in view of Lu, to minimize, 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; 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 1-4, 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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages). 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 PD-1 or PD-L1 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 Lu 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).
Lu teaches that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists (page 2, col. 3, para. 1, last 4 lines).
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 to be a TLR2 inhibitor, for the treatment, prevention, or minimization of progression of cancer in a subject, with an immunostimulant comprising PD-1 or PD-L1 antibody, as taught by Jackson in view of Lu. One of ordinary skill would have been motivated to do so in view of Copending ‘886’s disclosure of their compound; Bartlett’s disclosure of the compound is 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. 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 PD-1/PD-L1 inhibitors); and Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
Regarding instant claim 5, Jackson teaches a method of treatment of cancer. It flows from this art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding instant 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 instant 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 instant 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 instant claim 16, Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds.
Regarding instant claim 17, Jackson speaks to a method of treating a cancer caused by Human Papilloma Virus (HPV) (Jackson’s claim 16), reading on vaginal and cervical tumors. Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for rerating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding instant claim 18, Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for rerating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding instant claims 20 and 54, Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery and Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the Copending ‘886’s TLR2 inhibitor, as taught by Bartlett, the PD-1/PD-L2 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 Copending ‘886 s disclosure of their compound; Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Lu’s teachings of the benefits of co-administration of immunomodulators.
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 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 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
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, Lu discloses that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists. Therefore, it would be obvious from the art that co-administration of a TLR2 agonist with an immunostimulant PD-1/PD-L1 inhibitor would result in an improvement of the effectiveness of a treatment with the immunostimulants alone.
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 PD-1 or PD-L1 antibody would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Lu. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘886’s disclosure of their compound; Bartlett’s disclosure that Copending ‘886’s compound is 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 Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages); 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 Lu 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).
While Copending ‘886 in view of Bartlett, Jackson, and Lu 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 to be a TLR2 inhibitors, with a PD-1/PD-L1 inhibitor, as taught by Jackson in view of Lu, to minimize, 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; 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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages). 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 PD-1 or PD-L1 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 Lu 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).
Lu teaches that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists (page 2, col. 3, para. 1, last 4 lines).
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 TLR2 inhibitor for the treatment of progression of cancer in a subject, with an immunostimulant comprising PD-1 or PD-L1 antibody, as taught by Jackson in view of Lu. One of ordinary skill would have been motivated to do so in view of Copending ‘278’s disclosure of their TLR2 compound; Bartlett’s disclosure of the compound is 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. 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 PD-1/PD-L1 inhibitors); and Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
Regarding instant claim 5, Jackson teaches a method of treatment of cancer. It flows from this art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding instant 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 instant 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 instant 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 instant claim 16, Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds.
Regarding instant claim 17, Jackson speaks to a method of treating a cancer caused by Human Papilloma Virus (HPV) (Jackson’s claim 16), reading on vaginal and cervical tumors. Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for rerating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding instant claim 18, Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for rerating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding instant claims 20 and 54, Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery and Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the Copending ‘278’s TLR2 inhibitor, as taught by Bartlett, the PD-1/PD-L2 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 Copending ‘278 s disclosure of their compound; Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Lu’s teachings of the benefits of co-administration of immunomodulators.
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 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 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
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, Lu discloses that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists. Therefore, it would be obvious from the art that co-administration of a TLR2 agonist with an immunostimulant PD-1/PD-L1 inhibitor would result in an improvement of the effectiveness of a treatment with the immunostimulants alone.
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 PD-1 or PD-L1 antibody would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Lu. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘278’s disclosure of their compound; Bartlett’s disclosure that Copending ‘278’s compound is 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 Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages); 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 Lu 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).
While Copending ‘278 in view of Bartlett, Jackson, and Lu 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 to be a TLR2 inhibitors, with a PD-1/PD-L1 inhibitor, as taught by Jackson in view of Lu, to minimize, 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; 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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages). 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 PD-1 or PD-L1 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 Lu 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).
Lu teaches that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists (page 2, col. 3, para. 1, last 4 lines).
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 to be a TLR2 inhibitor, for the treatment, prevention, or minimization of progression of cancer in a subject, with an immunostimulant comprising PD-1 or PD-L1 antibody, as taught by Jackson in view of Lu. One of ordinary skill would have been motivated to do so in view of Copending ‘434’s disclosure of their compound; Bartlett’s disclosure of the compound is 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. 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 PD-1/PD-L1 inhibitors); and Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
Regarding instant claim 5, Jackson teaches a method of treatment of cancer. It flows from this art that identification of a subject who has cancer would occur prior to administration of any treatment of cancer.
Regarding instant 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 instant 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 instant 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 instant claim 16, Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds.
Regarding instant claim 17, Jackson speaks to a method of treating a cancer caused by Human Papilloma Virus (HPV) (Jackson’s claim 16), reading on vaginal and cervical tumors. Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for rerating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding instant claim 18, Lu discloses that currently, a clinical trial comprising PD-1/PD-L1 blockage for rerating breast cancer cutaneous metastasis is being planned (page 3, col. 1, para. 1, lines 6-10).
Regarding instant claims 20 and 54, Bartlett discloses a composition comprising their TLR2 inhibitor and further comprising a pharmaceutically acceptable diluent, carrier, or excipient suitable for inhalation or intranasal delivery and Lu discloses the benefits of co-administering a PD-1 inhibitor with a TLR2 agonist, such as the instant compounds. Therefore, it would have been prima facie obvious to one of ordinary skill to prepare a single formulation comprising the Copending ‘434’s TLR2 inhibitor, as taught by Bartlett, the PD-1/PD-L2 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 Copending ‘434 s disclosure of their compound; Bartlett’s disclosure of their pharmaceutical compositions comprising the instant TLR2 inhibitor; and Lu’s teachings of the benefits of co-administration of immunomodulators.
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 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 49, Jackson discloses their compositions may be administered intravenously (page 20, line 24).
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, Lu discloses that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists. Therefore, it would be obvious from the art that co-administration of a TLR2 agonist with an immunostimulant PD-1/PD-L1 inhibitor would result in an improvement of the effectiveness of a treatment with the immunostimulants alone.
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 PD-1 or PD-L1 antibody would improve survival, reduce tumor growth, and or reduce metastasis in a subject, as taught by Jackson in view of Lu. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in view of Copending ‘434’s disclosure of their compound; Bartlett’s disclosure that Copending ‘434’s compound is 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 Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists.
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 Lu et al. (Frontiers in Immunology, 2014, 5, Article 83, 4 pages); 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 Lu 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).
While Copending ‘434 in view of Bartlett, Jackson, and Lu 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 to be a TLR2 inhibitors, with a PD-1/PD-L1 inhibitor, as taught by Jackson in view of Lu, to minimize, 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; 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
Specification
Amendments to the specification are acknowledged and have been entered. No new matter has been introduced. The objection to the specification has been withdrawn.
Claims/ Claim Objections
Claim amendments are acknowledged. No new matter has been introduced.
Applicant’s arguments, see page 7, filed 01/29/2026, with respect to the objections to the claims have been fully considered and are persuasive. The objection of the claims has been withdrawn.
Claim Rejections - 35 USC § 112(b)
Applicant’s arguments, see pages 7-8, filed 01/29/2026, with respect to 35 USC § 112(b) rejections of the claims have been fully considered and are persuasive. The 35 USC § 112(b) rejections of the claims has been withdrawn.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 01/29/2026 have been fully considered but they are not persuasive.
Applicant argues that Barlett’s methods are drawn to the treatment of respiratory conditions and not to administration of their TLR2 inhibitor for the treatment of cancer, alone or in combination with a checkpoint inhibitor. Applicant argues Jackson’s methods are akin to immune response/ cancer vaccination and not therapies of preventing/treating cancer progression in combination with checkpoint inhibitors. Applicant further states Jackson offers no working examples of anti-cancer effects, and therefore a skilled person would not have been motivated to “develop/substitute Jackson’s compositions comprising TLR2 moiety to treat influenza and other infectious diseases and not cancer”. Applicant states there is no teaching, suggestion, or motivation in Jackson to explore TLR2 agonism as a direct cancer therapy, alone or in combination with a checkpoint inhibitor. Applicant states that Lu teaches TLR2 agonism would be deleterious to cancer treatment, and that no teaching in Lu suggests that agonists of TLR2 would be the TLR agonist most likely to succeed in cancer therapy. Applicant cites Yamazaki et al. (reference 1) and Chen Q et al. (reference 2) (see bottom of page 10 of remarks filed 01/29/2026) and states that these references cited by Lu teach TLR2 inhibition as deleterious for cancer immunology.
Contrary to what Applicant states, at a first glance, reference 1 (see pages 10-11 of remarks) does not state that TLR2 agonism prevents anti-tumor immunity; and neither does reference 2. Furthermore, these references were not relied upon for any rejections of the record.
Applicant further states that Lu does not show experimental data. Applicant cites “several failed clinical trials” however provides no specific details. Furthermore, these failed clinical trials were not relied upon for any rejections of the record. Applicant states the instant application relates to a “surprising effect that is achieved by the recited combination of a TLR2 agonist and a checkpoint inhibitor against cancer”.
Applicant states Fig. 1 shows a clear combination benefit for a PD1-Ab and Pam2CSK4 (TLR2/6 agonist – not the same as the instant compound of claim 1) compared to either component alone, and asserts that this improved effect is not taught or suggested by the prior art. – Applicant is advised that the Figure 1 cited (shown below) does not coincide with instant Figure 1 or with any figure in the disclosure and that Pam2CSK4 is not the same as the instant compound from claim 1.
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Applicant further presents a Fig. 2 (which does not coincide with Figure 2 of the Drawings in the disclosure, or any of the instant figures, and is difficult to read) (see below), to say that the combination shows a “dramatic and surprising combination effect”.
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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 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, Bartlett discloses the compound in instant claim 1 as a TLR2 agonist (page 2-3).
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).
Lu teaches that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists (page 2, col. 3, para. 1, last 4 lines). Lu discloses that TLR ligation not only initiates immune response, but also triggers negative regulatory path- ways; induction of these regulatory pathways represents a major obstacle in developing TLR agonists as cancer immunotherapeutics, and the promise of using TLR agonists to eradicate tumor cells probably won’t be realized unless we block the negative regulators like PD-L1 and tip the balance toward an overwhelming pro-inflammatory (anti-tumor) responses (page 2, col. 3, para. 3; and Figure 1). Lu specifically teaches that cancer immunologists are now exploring novel combinational therapies that combine TLR ligation with blockade of the negative regulators, such as PD-1.
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 PD-1 or PD-L1 antibody, in view of Lu. 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 Lu’s teaching that the promise of using TLR agonists to eradicate tumor cells probably won’t be realized unless we block the negative regulators like PD-L1 and tip the balance toward an overwhelming pro-inflammatory (anti-tumor) responses. 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 PD-1/PD-L1 inhibitors); and Lu’s disclosure that blocking PD-1/ PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists, and their disclosure that cancer immunologists are now exploring novel combinational therapies that combine TLR ligation with blockade of the negative regulators, such as PD-1.
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.
In response to Applicant’s Figures 1 and 2 (see pages 12-13 of the remarks filed 01/29/2026); the compound shown in the figure 1 is different from the compound in the instant claim, therefore, the graph is not commensurate with the scope of the claims. Figure 2 is blurry and difficult to read. Furthermore, these Figures 1 and 2 do not coincide with the Figures 1 and 2 of the original disclosure, and thus would need to be submitted as a declaration or affidavit in order to have any weight on the decision of patentability. Per MPEP 716.02(d): Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support."
While instant Figures 5 and 7 do show improved tumor volume reduction after combination treatment with A108 (instant compound in claim 1) and anti-PD-1 and PD-L1, respectively; in light of Lu’s teaching that blocking PD-1/PD-L1 signaling represents an opportunity to augment the anti-tumor effects of TLR agonists; and their suggestion that the promise of using TLR agonists to eradicate tumor cells probably won’t be realized unless we block the negative regulators like PD-L1 and tip the balance toward an overwhelming pro-inflammatory (anti-tumor) responses; these results are not entirely unexpected. Applicant is advised, for the data to be persuasive in overcoming the obviousness rejection of record, Applicant is required to demonstrate that the reduction in tumor growth results from an unexpected synergism between the instant compound A108 and the anti-PD-1, PD-L1, or CTLA-4, and not just the expected additive effect of combining the two treatments.
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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” discussed in the 103 section above.
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).
With regards to the “unexpected results” arguments, see the 103-section arguments above.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L. Klinkel can be reached at (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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