DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 26 June 2026 have been entered. Claims 1-6, 10, 12-21, 27, 29-30, and 48 were previously pending in the application. Claims 4-6, 10, 12, 27, 29 have been cancelled, and new claims 55-60 have been added by Applicant. Claims 1-3, 13-21, 30, 48, and 55-60 are currently pending in the application. Claims 1, 30, and 48 are independent claims.
The election of Group I, drawn to a synthetic therapeutic bacteriophage and a live biotherapeutic, remains in effect in the instant application.
The following election of species remains in effect in the instant application:
therapeutic agents: a. a binding protein;
binding protein activities: c. inhibits an immune checkpoint molecule: i. Immune checkpoint molecules: 6. PD-L1.
Claims 48 remains withdrawn and claim 60 is newly withdrawn from consideration as being directed to a nonelected invention, there being no allowable generic or linking claim.
Claim 13-16, 19, and 21 remain withdrawn from consideration as being directed to a nonelected species, there being no allowable generic or linking claim.
Claims 1-3, 17-18, 20, 30, and 55-59 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/CA2021/051415, filed 07 October 2021, which claims priority to U.S. Provisional Application Nos. 63/088,643, filed 07 October 2020, 63/161,543, filed 16 March 2021, and 63/215,176, filed 25 June 2021. Thus, the earliest possible priority for the instant application is 07 October 2020.
Claim Objections
Amended claim 18 is objected to because of the following informalities: claim 18 recites a list of immune checkpoint molecules, wherein a part of the list is presented in bold type, which is not an acceptable format for claims. See MPEP 714 and 37 C.F.R. 1.121(c), which outlines the specific acceptable markings for amendments to the claims (e.g., underlining of inserted text) and does not indicate that bold text is an acceptable marking. Appropriate correction is required.
New claim 56 is objected to because of the following informalities: claim 56 recites, “a coating proteins” in line 2 such that the indefinite article “a” conflicts with the plural “proteins”. Appropriate correction is required.
Specification
The objection to the specification of the disclosure for reciting “Figures 14A-14H” in [0036] and reciting trade names and/or marks used in commerce without the accompanying symbols and/or generic terminology is withdrawn in view of the amendment to the specification. The amendment to the specification of the disclosure filed 26 June 2026 has been entered.
Claim Rejections - 35 USC § 112(b)
The rejection of amended claim 18 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting “the immune checkpoint molecule is selected from”, is withdrawn in view of Applicant’s amendments to the claims such that claim 18 now recites, “wherein the immune checkpoint molecule is” with the list joined by the linker “or”. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Claim Rejections - 35 USC § 102
The rejection of amended and cancelled claims 1-2, 12, 17-18, and 20 under 35 U.S.C. 102(a)(1) as being anticipated by Kalim et al. 2019, Cytotechnology, 71(3), 705-722, IDS, is withdrawn in view of Applicant’s amendment to claim 1 to recite, “non-infectious” and “wherein the non-infectious synthetic therapeutic bacteriophage does not display a wild-type coating protein pIII”.
Claim Rejections - 35 USC § 103
The rejection of amended, original, and cancelled claims 1, 3-6, 10, and 30 under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Kalim et al. [2019, Cytotechnology, 71(3), 705-722, IDS]; as evidenced by and/or in view of Hess & Jewel [2019, Bioengineering & Translation Medicine, 5, e10142, 1-15] and Mai-Prochnow et al. [2015, FEMS Microbiology Reviews, 39, 465-487]; is withdrawn in view of Applicant’s amendment to claim 1 to recite, “non-infectious” and “wherein the non-infectious synthetic therapeutic bacteriophage does not display a wild-type coating protein pIII”.
**The following new rejection is necessitated by Applicant’s amendments to the claims.
Amended, original, and new claims 1-3, 17-18, 20, 30, and 55-59 are newly rejected under 35 U.S.C. 103 as being unpatentable over Larocca et al. [2001, Molecular Therapy, 3(4), 476-484] in view of Kalim et al. [2019, Cytotechnology, 71(3), 705-722, IDS, cited in a prior action]; Hess & Jewel [2019, Bioengineering & Translation Medicine, 5, e10142, 1-15, cited in a prior action]; Gandra et al. [2013, Small, 9(2), 215-221]; and Gao et al. [2002, Proceedings of the National Academy of Science, 99(20), 12612-12616].
Regarding amended, original, and new claims 1, 2, 17, 18, 20, and 59, Larocca teaches a non-infectious synthetic therapeutic filamentous bacteriophage displaying at least a first therapeutic agent, wherein the first therapeutic agent is epidermal growth factor (EGF), a binding protein that binds to epidermal growth factor receptor (EGFR), which is a protein involved in development of cancer [abstract], wherein the first therapeutic agent is fused to a carboxy-terminal fragment of coating protein pIII of the synthetic bacteriophage [abstract, pg 482 col 2 ¶ 1], and wherein the non-infectious synthetic therapeutic bacteriophage does not display a wild-type coating protein pIII [abstract, pg 478 col 1 ¶ 3, pg 482 col 2 ¶ 1, pg 483 col 1 ¶ 3, Figure 1, 2, 3].
Larocca does not teach wherein the first therapeutic agent the elected binding protein that inhibits an immune checkpoint molecule, PD-L1.
However, Kalim teaches a synthetic filamentous bacteriophage displaying an anti-PD-L1 antibody fragment therapeutic agent [abstract].
Kalim teaches that binding of PD-L1 and PD-1 inhibits proliferation and activation of T cells and results in cell exhaustion, which can be reversed by blocking PD-L1/PD-1 interaction with single chain variable fragments (scFv) fusion proteins against PD-L1, thereby inhibiting an immune checkpoint in cancer therapy [abstract, pg 706 col 1 ¶ 1, Figure 1]. Kalin further teaches that the blockade of PD-L1 by scFv proteins can inhibit cell growth and eventually induce cell death to inhibit tumor cells in cancer therapy [pg 720 col 1 ¶ 2]. Kalim also teaches wherein the PD-L1 antibodies can be used as a potent carrier to transport anti-tumor agents to cancer cells, such as therapeutic gene delivery [abstract, pg 706 col 2 ¶ 1, pg 718 col 2 ¶ 1, pg 720 col 1 ¶ 3- col 2 ¶ 1]. Therefore, given the teachings of Kalim to use PD-L1 antibodies for both blocking PD-L1-PD-1 interactions and to target cancer cells for therapeutic gene delivery, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use an anti-PD-L1 antibody fragment to target cancer cells for gene delivery, to inhibit PD-L1/PD-1 immune checkpoints, and to inhibit cell growth and eventually induce cell death to inhibit tumor cells in cancer therapy.
Regarding amended claim 3, Larocca and Kalim teach the limitations of claim 1, Additionally, Larocca teaches wherein the filamentous bacteriophage has an M13 origin of replication [Figure 1] and wherein the EGF is fused to a filamentous pIII coat protein C-terminal domain from an MG4 phage [pg 478 col 1 ¶ 3], but does not teach wherein the bacteriophage is specifically an M13.
Kalim teaches wherein the phage displaying the anti-PD-L1 scFv is an M13 phage [pg 707 col 2 ¶ 1, pg 708 col 1 ¶ 2, pg 709 col 1 ¶ 1]].
Hess teaches that filamentous phages used for phage display therapeutics, such as M13 and fd, comprise a bacteriophage secretion system comprising bacteriophage machinery, including a bacteriophage genome encoding coat proteins, wherein progeny bacteriophage are secreted by progeny genomes exiting the cell envelope and thereby acquiring coat proteins [column 6 ¶ 1]. Hess additionally teaches the use of M13 phage to promote a stronger inflammatory response capable of breaking tolerance, wherein filamentous phage crosses through blood vessels, making it especially attractive for cancer applications [pg 10 col 2 ¶ 1].
Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use an M13 filamentous phage to display an anti-cancer therapeutic agent to promote a stronger inflammatory response capable of breaking tolerance.
Regarding previously presented claim 30, Larocca teaches recombinant IL1-Blue host bacteria used to produce the synthetic therapeutic bacteriophages/phagemid particles, wherein the bacteria secrete the synthetic therapeutic bacteriophage of claim 1 into the culture supernatant [pg 477 col 2 ¶ 2]. Therefore, the bacteria taught by Larocca inherently comprise a bacteriophage secretion system capable of secreting the synthetic therapeutic bacteriophage.
Regarding new claim 55, Larocca and Kalim teach the limitations of independent claim 1, but do not teach wherein the therapeutic bacteriophage displays a second therapeutic agent.
Gandra teaches a filamentous bacteriophage as a carrier for both cancer-targeting peptides and photosensitizers for use in selective cancer cell killing by photodynamic therapy, wherein each phage displays both the cancer targeting peptide and the photosensitizer [Title, Scheme 1]. Gandra also teaches that the combination of cancer-targeting peptide and photosensitizer displayed on a phage produces a target-specific photosensitizer that can be used both in vitro and in vivo to selectively abolish a tumor by producing cytotoxic 1O2 upon illumination with an appropriate wavelength of light at the target site [pg 219 col 1 ¶ 2]. Therefore, given the teachings of Gandra to use a first therapeutic agent which is a photosensitizer and a second therapeutic agent which is a tumor-targeted peptide to direct a phage to the site of a cancer cell to selectively abolish a tumor, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to produce a synthetic therapeutic bacteriophage displaying a second therapeutic agent.
Regarding new claims 56-57, Gandra teaches wherein the second therapeutic agent (i.e., a tumor-targeting peptide) is displayed on a coating protein that does not display the first therapeutic agent (i.e., a photosensitizer), wherein the major coat protein pVIII partially displays photosensitizer and partially displays only the cancer-targeting peptide [Scheme 1C].
Regarding new claim 58, Gandra teaches that the major coat proteins pVIII compose the side wall of the phage while the four other minor coat proteins (i.e., pIII, pVI, pVII, and pIX) constitute the two distal ends, and that the surface of the phage can be genetically modified by fusing a foreign peptide to the N-terminal end of the coat proteins [pg 215 col 2 ¶ 1]. However, none of Larocca, Kalim, Hess, nor Gandra teaches specifically wherein the second therapeutic agent is displayed on the pIX coating protein.
Gao teaches that display on pIX is advantageous because pIX is a small 32-amino acid peptide such that the wild-type pIX provides little steric interference and is more accessible to targets [pg 12615 col 2 ¶ 4]. Gao also teaches that pIX have a relatively low likelihood of hydrophobic and/or electrostatic interactions which would contribute to nonspecific binding activities [pg 12615 col 2 ¶ 4]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to display an agent on pIX to minimize steric interference and non-specific binding.
Given the motivation taught by Kalim to use an anti-PD-L1 antibody fragment to target cancer cells for gene delivery, to inhibit PD-L1/PD-1 immune checkpoints, and to inhibit cell growth and eventually induce cell death to inhibit tumor cells in cancer therapy; the motivation taught by Hess to use an M13 filamentous phage to display an anti-cancer therapeutic agent; the motivation taught by Gandra to produce a synthetic therapeutic bacteriophage displaying a second therapeutic agent; and the motivation taught by Gao to display an agent on pIX to minimize steric interference and non-specific binding; it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the non-infectious synthetic therapeutic bacteriophage of Larocca to display an anti-PD-L1 antibody fragment and a second therapeutic agent, wherein the second therapeutic agent is displayed on pIX, and wherein the filamentous phage is an M13 phage with a reasonable expectation of success.
Insofar as Applicant’s arguments apply to this new grounds of rejection, Applicant argues that:
the phage display technology as disclosed by Kalim is dependent on the ability of the phages to infect bacteria and not to a carboxy-terminal fragment of coating protein pIII to provide a non-infectious synthetic therapeutic bacteriophage as claimed;
there is no teaching in Hess regarding non-infectious synthetic therapeutic bacteriophage that does not comprise a wild-type pIII protein and in which a therapeutic agent is fused to a carboxy-terminal fragment of coating protein pIII; and
the advantageous effects of a non-infectious synthetic therapeutic bacteriophage with various therapeutic proteins such as immune checkpoint proteins attached to a carboxy-terminal fragment of pIII protein capable of inducing a strong antitumor immune response and mediating tumor clearance in animal cancer models could not have been predicted from the teachings of Kalim, Hess, and Mai-Prochnow.
However, this is not agreed.
In response to Applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). 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). Further, 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 addition, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, regarding Applicant’s arguments 1)-2), note that neither Kalim nor Hess were relied on for teaching a non-infectious synthetic bacteriophage which does not display a wild-type coating protein pIII. Larocca was cited for teaching a non-infectious synthetic therapeutic filamentous bacteriophage displaying at least a first therapeutic agent, wherein the first therapeutic agent is epidermal growth factor (EGF), a binding protein that binds to epidermal growth factor receptor (EGFR), which is a protein involved in development of cancer [abstract], wherein the first therapeutic agent is fused to a carboxy-terminal fragment of coating protein pIII of the synthetic bacteriophage [abstract, pg 482 col 2 ¶ 1], and wherein the non-infectious synthetic therapeutic bacteriophage does not display a wild-type coating protein pIII [abstract, pg 478 col 1 ¶ 3, pg 482 col 2 ¶ 1, pg 483 col 1 ¶ 3, Figure 1, 2, 3].
Regarding Applicant’s argument 3), as discussed above, Larocca teaches a non-infectious synthetic therapeutic bacteriophage. Additionally, Kalim was cited for teaching the motivation to use an anti-PD-L1 antibody fragment to target cancer cells for gene delivery, to inhibit PD-L1/PD-1 immune checkpoints, and to inhibit cell growth and eventually induce cell death to inhibit tumor cells in cancer therapy. Hess additionally was cited for teaching Hess to use an M13 filamentous phage to display an anti-cancer therapeutic agent. Hess further teaches wherein phages delivering an immunostimulatory glycolipid convey antitumor effects in a mouse melanoma model [Figure 4]. Gandra was additionally cited for teaching the use of filamentous bacteriophage to target cancer cells and to selectively abolish a tumor. Accordingly, an ordinarily skilled artisan at the time of filing the instant application would have had a reasonable expectation of success for a non-infectious synthetic therapeutic bacteriophage according to Larocca, with various therapeutic proteins such as immune checkpoint proteins as taught by Kalim, to be able to induce a strong antitumor response and mediate tumor clearance in an animal model.
Therefore, Applicant’s arguments do not overcome a finding of obviousness over Larocca, Kalim, Hess, Gandra, and Gao.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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