DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1) A request for continued examination under 37 C.F.R 1.114, including the fee set forth in 37 C.F.R 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 C.F.R 1.114, and the fee set forth in 37 C.F.R 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 C.F.R 1.114. Applicant’s submission filed on 03/25/25 has been entered.
Applicants’ Amendment
2) Acknowledgment is made of Applicant’s amendment filed 03/25/25 in response to the final Office Action mailed 12/26/24.
Status of Claims
3) Claim 1 has been amended via the amendment filed 03/25/2025. It is noted that claim 1, as amended, does not require the administration of a single dose of the recited composition in the claimed method.
Claims 1, 4, 5, 7, 8, 10, 12 and 18-22 are pending.
Claims 1, 4, 5, 7, 8, 10, 12 and 20-22 are under examination.
Prior Citation of Title 35 Sections
4) The text of those sections of Title 35 U.S. Code not included in this action can be found in a prior Office Action References.
Prior Citation of References
5) The references cited or used as prior art in support of one or more rejections in the instant Office Action and not included on an attached form PTO-892 or form PTO-1449 have been previously cited and made of record.
Objection(s) Withdrawn
6) The objection to claim 1 and the specification set forth in paragraph 8 of the Office Action mailed 12/26/24 is withdrawn in light of Applicant’s amendment to claim 1.
Rejection(s) Moot
7) The provisional rejection of claims 1, 4, 5, 7, 8, 10 and 20-22 set forth at paragraph 26 of the Office Action mailed 06/03/24 and maintained at paragraph 35 of the Office Action mailed 12/26/24 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 6, 5, 1, 2 and 13-19 of U.S application 17791282 in view of Brahmer et al. (J. Clin. Oncol. 28: 3167-3175, 2010, of record) (Brahmer et al., 2010) and Bender (US 20140248211 A1, of record) is moot in light of the abandoned status of the ‘282 application.
Rejection(s) Withdrawn
8) The rejection of claims 1, 4, 5, 7, 8, 10, 12 and 20-22 set forth at paragraph 35 of the Office Action mailed 12/26/24 under 35 U.S.C § 112(a) or 35 U.S.C § 112 (pre-AlA), first paragraph, as containing new matter is withdrawn in light of Applicant’s amendments to the base claim 1.
9) The rejection of claim 1 set forth at paragraph 37(a) of the Office Action mailed 12/26/24 under 35 U.S.C § 112(b) or 35 U.S.C § 112 (pre-AlA), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment to the claim.
10) The rejection of claim 1 set forth at paragraph 37(b) of the Office Action mailed 12/26/24 under 35 U.S.C § 112(b) or 35 U.S.C § 112 (pre-AlA), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment to the claim.
It is noted that the current amendment changes the scope of claim 1 in that the composition administered as recited is not required to be a ‘single dose’.
11) The rejection of claims 4, 5, 7, 8, 10, 12 and 20-22 set forth at paragraph 37(c) of the Office Action mailed 12/26/24 under 35 U.S.C § 112(b) or 35 U.S.C § 112 (pre-AlA), second paragraph, as being indefinite is withdrawn in light of Applicant’s amendment to claim 1.
12) The rejection of claims 1, 4, 5, 7, 8, 10, 12 and 20-22 set forth at paragraph 28 of the Office Action mailed 06/03/24 and maintained at paragraph 33 of the Office Action mailed 12/26/24 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 11, 3, 2, 1, 14, 7-9, 6, 5 and 12 of US patent 10441645 B2 (of record) in view of Brahmer et al. (J. Clin. Oncol. 28: 3167-3175, 2010, of record) (Brahmer et al., 2010) is withdrawn in light of Applicant’s amendment to claim 1. Applicant is referred to the new rejection set forth in this Office Action to address the claim(s) as amended.
Applicant contends that the combination of one vaccine encoding tumor antigen MSLN with a checkpoint inhibitor does not render obvious the combination of another vaccine encoding stroma antigen VEGFR-2 with a checkpoint inhibitory antibody against PD-1/PD-L1. Applicant asserts that VEGFR-2 is a stroma antigen and the vaccine encoding VEGFR-2 is an antiangiogenic treatment rather than a treatment directed to the tumor antigen of MSLN and therefore the mechanism of action of these two vaccines differs.
Applicant’s arguments have been considered, but are not persuasive. Contrary to Applicant’s assertion, the treatment method of the identified claims of the ‘645 patent including claims 11 and 12 comprises administering S. typhi Ty21a encoding human VEGFR-2, the very same human VEGFR-2 as recited in instant claims, and a checkpoint inhibitory antibody. Since the human VEGFR-2 of the ‘645 patent and the instantly recited human VEGFR-2 are one and the same, they are expected to have the same anticancer therapeutic effects. The teachings of the references as a whole render obvious instant claims as is set forth previously. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either obviousness or anticipation, obviousness in the instant rejection, has been established. MPEP 2112.01.
Rejection(s) under 35 U.S.C § 103 Maintained
13) 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 of this title, 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 claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 148 USPQ 459, that are applied for establishing a background for determining obviousness under 35 U.S.C § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or unobviousness.
14) The rejection of claims 1, 4, 5, 7, 8, 10, 12 and 20-22 under set forth at paragraph 39 of the Office Action mailed 12/26/24 under 35 U.S.C § 103 as being unpatentable over Schmitz-Winnenthal et al. (OncoImmunology 4:4, e1001217-1 to e1001217-13, published online 16 March 2015, of record) (Schmitz-Winnenthal et al., March 2015, of record) as evidenced by Lubenau et al. (WO 2013091898 A1, of record) (‘898) and in view of Brahmer et al. (J. Clin. Oncol. 28: 3167-3175, 2010, of record) (Brahmer et al., 2010) and Bender (US 20140248211 A1, of record) is maintained.
Applicant refers to different parts of the art rejection of record and submits the following arguments. Applicant’s arguments have been considered, but are not found to be persuasive.
First, it is noted that claim 1, as amended currently, deletes the ‘single’ dose requirement.
Applicant cites case law, refer to the Graham inquiries under 35 U.S.C § 103(a) and MPEP § 2142 and contend that rejections on obviousness cannot be sustained with mere conclusory statements; instead, must be some articulated reasoning with some rational underpinning to support the legal conclusions of obviousness. Applicant states that to reach a proper determination under 35 U.S.C § 103, the Office must step backward in time and into the shoes worn by the hypothetical person of ordinary skill in the art when the invention was unknown and just before it was made and make a determination whether the claimed invention ‘as a whole’ would have been obvious at the time to that person. Applicant cites case law and asserts that a patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was independently known in the prior art. Applicant states that use of hindsight must be avoided in establishing the reason for combining elements from two or more prior art documents; the legal conclusion must be reached on the basis of the facts gleaned from the prior art, at the time of the invention, and not on the basis of the application text.
In response, the rejection with the articulated reasoning was set forth after conducting full analysis and all basic factual enquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 17 (1966). With regard to Applicant’s statement on the hindsight, it must be noted that a 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 applicant's disclosure, such a reconstruction is proper. In re McLaughlin, 443 F.2d 1392, 1395, (CCPA 1971). Applicant has not explained what knowledge gleaned allegedly from the specification is not found in either of the references to arrive at the claimed method. In the instant rejection, only the knowledge available to a person of ordinary skill at the time of invention is used.
Applicant states [Emphasis by Applicant]:
.... the Examiner alleges that Schmitz-Winnenthal et a/. discloses VXM01, an oral vaccine against VEGFR-2, for use in patients with pancreatic cancer. VXMO1 has anti-angiogenic activity, as the Examiner acknowledged on page 8, line 5 of the Action. The Examiner acknowledges that Schmitz-Winnenthal et al. is silent on further administering an antibody against PD-1. (See page 12 of the Action.)
Applicant’s above statement is evidence that the Graham v. Deere analysis has indeed been performed by the Office. Schmitz-Winnenthal et a/. did teach that VXM01 has anti-angiogenic activity. Additionally, Schmitz-Winnenthal’s (March 2015) VXM01 was known in the art at the time of the invention to show consistent anti-angiogenic and anti-tumor activity in different tumor types in several animal studies. For example, see the 3rd full sentence in 2nd full paragraph under the section ‘INTRODUCTION’ on page 2 of the attached reference of Schmitz-Winnenthal et al. J. Clin. Oncol. 31 (15 Suppl): Developmental Therapeutics - Immunotherapy, # 3090, 20 May 2013 (Schmitz-Winnenthal et al., May 2013). It is noted that this evidentiary reference of Schmitz-Winnenthal et al. (May 2013) is co-authored by H. Lubenau, the inventor of the instant application. Thus, the anti-angiogenic activity and the anti-tumor activity shown in different tumor types are intrinsic to and inseparable from the prior art VXM01.
With regard to the teachings of Brahmer et al., Applicant states that Brahmer et al. does not provide convincing evidence that its anti-PD-1 antibody was an art-known agent having demonstrated anti-cancer effects as alleged in the Office Action.
It is noted that Applicant has failed to produce any convincing evidence that the anti-PD-1 antibody, MDX-1106, administered by Brahmer et al. was not an art-known anti-PD-1 antibody before the effective filing date of the instant application. Applicant refers to Brahmer’s Abstract, ‘Purpose’ and ‘Patients and Methods’ sections and acknowledges Brahmer’s anti-PD1-blockade in patients having treatment-refractory solid tumors. Applicant refers to Brahmer’s 1st full paragraph in right hand column of page 3172, Abstract, ‘Results’ section, and Table 2 on page 3169 and further acknowledges that one of 39 patients tested in Brahmer’s clinical study had “complete response”, two patients had “partial responses” and two patients had “lesional tumor regression”. With these statements on Brahmer’s disclosure, Applicant concludes: “Thus, responses were seen in 5 out of 39 patients”.
First, the Office notes that MDX-1106, also known as BMS-936558 / ONO-4538, that was administered in Brahmer’s clinical study was indeed an art-known anti-PD-1 antibody. See at least the section entitled ‘MDX-1106’ on page 3168 of Brahmer et al. Second, the complete and partial responses as well as the lesional tumor regression responses demonstrated by Brahmer et al. with this anti-PD-1 antibody in patients with advanced treatment-refractory solid tumors are indicative of the ‘anti-cancer’ therapeutic effects in said cancer patients resulting from Brahmer’s administration of the art-known MDX-1106 anti-PD1 antibody.
Applicant argues that Brahmer et al. is totally silent on combinations of an anti-PD-1 antibody therapy with any treatment targeting VEGFR-2, let alone a Salmonella-based vaccine encoding VEGFR-2. By stating so, Applicant is arguing as though Brahmer et al. is applied in the art rejection as an anticipatory art. However, it is not.
Applicant further asserts that Brahmer et al. teaches that in order for anti-PD-1 antibodies to generate an anti-tumor response, PD-L1 needs to be expressed within the tumor. The abstract, the last sentence of ‘Results’, and lines 6-7 of 2nd paragraph in left column on page 3168 of Brahmer et al. are stated as disclosing that the expression of tumor cell surface B7-H1, i.e., PD-L1, the ligand to PD-1, in nine patients examined appeared to correlate with the likelihood of response to treatment. With these, Applicant states that Brahmer thus discloses that PD-L1 expression is required for anti-tumor responses upon treatment with anti-PD-1 antibodies. Applicant submits that there is nothing in either of the cited references to indicate whether or not this would occur if VXM01 is administered.
With regard to these arguments, the following teachings of Brahmer et al. must be noted. See 2nd half of 1st full paragraph on page 3168; the last full sentence of the paragraph bridging the two columns of page 3170; and the last sentence of ‘Results’ section under ABSTRACT on page 3167 of Brahmer et al. [Emphasis added]:
B7-H1 is highly upregulated in many murine and human tumors (either in tumor cells or nontransformed cells in the tumor microenvironment such as antigen-presenting cells) …… These findings have focused attention on PD-1:B7-H1 blockade as a strategy for cancer immunotherapy. On the basis of these considerations, we initiated a phase I clinical trial of PD-1 blockade with the fully human mAb MDX-1106 in 39 patients with advanced treatment-refractory solid tumors. We report here the safety, antitumor activity, ….. from this trial.
In this small sample size, the correlation between membranous B7-H1 expression on tumor cells and the likelihood of tumor regression following PD-1 blockade suggested potential significance..
In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment.
These teachings of Brahmer et al. available in the art at the time of the invention documented that B7-H1, i.e., PD-L1, is expressed intrinsically on tumor cells, i.e., in the absence of, independent of, or without the administration of VXM01. This knowledge gleaned from the art is consistent with and supported by others in the art. For example, WO 2018/167290 A1, naming Heinz Lubenau as the inventor, taught the following (see the sentences bridging pages 1 and 2) [Emphasis added]:
.... PD-L1 is extensively expressed on the surface of various types of cancer cells, which use the PD-1/PD-L1 signaling axis to escape the host immune system. Expression of PD-L1 was shown to correlate with disease stage and poor patient prognosis.
Brahmer’s clinical study conducted in human patients with advanced cancer patients did demonstrate that the administered art-known MDX-1106 anti-PD1 antibody checkpoint inhibitor had ‘antitumor activity’. Furthermore, contrary to Applicant’s assertion, it is clear that Brahmer’s clinical evaluation using the art-known MDX-1106 anti-PD-1 antibody checkpoint inhibitor in advanced cancer patients is more than a safety evaluation since it includes the demonstration of the therapeutic PD-1 blockade by the art-known MDX-1106 anti-PD-1 antibody in said cancer patients already possessing tumor cells expressing therein the B7-H1, i.e., PD-L1, resulting in the complete and partial responses as well as the lesional tumor regression responses.
With regard to the disclosure of Bender, Applicant contends that Bender does not disclose any combination of anti-PD1 antibody and Vaximm GmbH’s VXM01 vaccine, let alone in a manner that would provide the skilled person with a reasonable expectation of success that the combined treatment would be more effective than the single treatment or that the combination would act “synergistically” at the time of the invention. Applicant states that not all combined treatments are warranted due to either adverse effects or to little improvement in treatment outcomes. Applicant further points to claim 1 of Bender and states that Bender refers to administering a therapeutic agent and an intracellular permeation enhancing agent. Applicant points to claims 19-22 of Bender and acknowledges that anti-PD-1 antibodies are a part of a list of 40 antibody therapeutic agents among other agents or any combination thereof. Applicant notes that Bender at paragraphs [0050], [0224] to [0232] and claims 28-29 further refer to a long list of immunotherapeutic agents that includes a cancer vaccine, a tumor antigen, and an adjuvant among others. Applicant opines that this type of broad disclosure provides no effective guidance for a person of ordinary skill in the art and it does not lead to a specific combination of anti-PD-1 antibody and VXM01 without the use of impermissible hindsight. Applicant asserts that a person skilled in the art knows that not each and every possible combination of the listed therapeutic agents and immunotherapeutic agents can be used in combination and would result in an effective combination, wherein the immunotherapeutic agent further enhances the therapeutic effect of the therapeutic agent.
Applicant refers to Figures 23-25 and section [00170] of the as-filed specification and submits that the instant application demonstrated for the first time a synergistic effect of VXM01 in combination with the checkpoint inhibitory anti-CTLA4 antibody. Applicant refers to Figure 30 of the as-filed specification and states that both PD-1 and PD-L1 have been shown to be upregulated in the tumor following vaccination with VXM01 and it is reported that this clearly indicates that VXM01 treatment increases susceptibility of tumors towards the treatment with anti-PD-1 and anti-PD-L1 checkpoint inhibitors. Applicant further submits that inhibitory signals mediated by PD-1 expressed on T cells upon ligation with PD-L1 on tumor cells inhibits T cell proliferation and effector functions. Applicant states that while VXM01 elicits T cell responses, the increased PD-L1 expression in tumors together with the increased PD-1 positive T cells within the tumor detected in the instant application clearly show that the VXM01 elicited T cell responses would be increased by a PD-1/PD- L1 blockade and prevention of the inhibitory signal otherwise mediated by PD-1 on T cells in the presence of PD-L1. Applicant contends that the addition of an anti-PD-1 antibody without PD-L1 expression would not have provided a beneficial effect for the patient. Applicant asserts that the skilled artisan had no reasonable expectation of success with regard to a beneficial combinatorial treatment effect of VXM01 and an anti-PD-1 or anti-PD-L1 checkpoint inhibitory antibody since it was not known prior to the instant application that Salmonella-based vaccine encoding VEGFR-2, such as VXM01, used for antiangiogenic therapy acts “synergistically” with a checkpoint inhibitor and more importantly that PD-1 and PD-L1 expression are increased following VXM01 vaccination. Applicant states that this is in line with the observation in Brahmer et a/. that PD-L1 expression correlates with anti-PD-1 antibody efficacy and concludes that in the absence of the information provided for the first time in the instant application that PD-L1 is increased upon vaccination with VXM01, a person of ordinary skill in the art would not have been motivated to combine VXM01 with an antibody blocking the PD-1/PD-L1 interaction.
In response, the Office agrees that PD-L1 expression on cancer cells correlates with anti-PD-1 antibody efficacy as per the teachings of and the demonstration by Brahmer et al. set forth supra. However, contrary to Applicant’s statement that the addition of an anti-PD-1 antibody without PD-L1 expression would not have provided a beneficial effect for the patient, Brahmer’s demonstration documented that an art-known anti-PD-1 antibody, MDX-1106, exerts beneficial antitumor effect likely via interaction with the PD-L1 already expressed naturally on cancer cells, i.e., independent of without the need for VXM01.
Most importantly, contrary to Applicant’s statements, there is no evidence within the as-filed specification showing that: (1) the combination of VXM01 and an anti-PD-1 antibody checkpoint inhibitor acted “synergistically” in the treatment of a human patient against cancer; and (2) the combination of VXM01 and an anti-PD-1 antibody checkpoint inhibitor resulted in an effective combination, wherein the immunotherapeutic agent further enhanced the therapeutic effect of the therapeutic agent as asserted. Figure 30 of the as-filed specification referred to by the Applicant is of the PD-L1 mean fold induction in tumor samples from animals treated with the combination of VXM01 and cyclophosphamide (CYP). Nothing in the as-filed specification or in the art indicates that CYP and anti-PD-1 antibody are structurally identical. Figures 23-25 of the as-filed specification are not pertinent to the claimed method which includes the administration of a checkpoint inhibitor antibody against PD-1. None of Figures 23-25 of the as-filed specification demonstrate the asserted ‘synergistic effect’ of VXM01 in combination with the required antibody against PD-1.
Applicant asserts that neither Brahmer et al. nor Bender expressly or inherently teach the person of ordinary skill in the art to specifically combine VXM01 with anti-PD-1 antibodies in the expectation to generate an anti-cancer treatment with increased efficacy, thereby arriving at the presently claimed invention. Applicant submits that the person of ordinary skill in the art would not combine one cancer treatment with another cancer treatment, unless the mechanism of action suggests a beneficial or advantageous effect of the combination. Applicant states that a person of ordinary skill in the art would further know that the addition of an anti-PD-1 antibody without PD-L1 expression would not have provided a beneficial effect for the patient; this information was only present based on the finding of an increased expression of PD- L1 upon VXM01 vaccination demonstrated in the instant application, not on the basis of the facts gleaned from the cited references. Applicant acknowledges that Bender discloses VXM01 cancer vaccine, but merely as one of multiple listed examples of immunotherapeutic agents that can be used in cancer therapy. Applicant also acknowledges that Bender discloses anti-PD-1 antibody, but merely as one of listed multiple examples that can be used in antibody-based anticancer therapies.
In response, Bender taught the administration of the two specific elements recited in the instant method claims. The open claim language ‘the method comprising’ and ‘a composition comprising’ in instant claim 1 does not exclude an intracellular permeation enhancing agent. Bender’s composition contains (see lines 10-22 of section [0271]) [Emphasis added]:
..... a therapeutically effective amount of the therapeutic agent ...... and ... the immunotherapeutic agent .... together with a suitable amount of a carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
The disclosed two specific species, i.e., the VXM01 cancer vaccine immunotherapeutic agent and the anti-PD-1 therapeutic antibody agent, are expressly identified by naming them, and their administration in the method disclosed therein are expressly disclosed by Bender. For example, see at least claims 27, 28, 20 and 1; and sections [0040], [0228] and [0050]. In Merck & Co. v. Biocraft Labs., 874 F.2d 804, 807, 10 USPQ2d 1843, 1846 (Fed. Cir. 1989), it was held that claims directed to diuretic compositions comprising a specific mixture of amiloride and hydrochlorothiazide were obvious over a prior art reference expressly teaching that amiloride was a pyrazinoylguanidine which could be coadministered with potassium excreting diuretic agents, including hydrochlorothiazide which was a named example, to produce a diuretic with desirable sodium and potassium eliminating properties. In the instant case, the VXM01 cancer vaccine immunotherapeutic agent and the anti-PD-1 therapeutic antibody agent are expressly identified in Bender by naming them. At the time of the invention, the VXM01 cancer vaccine immunotherapeutic agent was already demonstrated in the art to have intrinsic anti-angiogenic and anti-tumor activities by Schmitz-Winnenthal et al. (2015 and May 2013); and the antitumor activity and the tumor-regression effect of an art-known anti-PD1 therapeutic antibody agent was already demonstrated by Brahmer et al. (2010). With the specific identification by naming the immunotherapeutic VXM01 cancer vaccine agent species and the therapeutic anti-PD-1 antibody agent species, Bender disclosed a method of treating cancer in a human in need of such treatment comprising enhancing the effect of the therapeutic agent by administering the immunotherapeutic agent. For example, see lines 6-13 of section [0233] of Bender. Per MPEP, the closer the physical and/or chemical similarities between the claimed species or subgenus and any exemplary species or subgenus disclosed in the prior art, the greater the expectation that the claimed subject matter will function in an equivalent manner to the genus. See e.g., Dillon, 919 F.2d at 696, 16 USPQ2d at 1904. A claimed compound may be obvious because it was suggested by, or structurally similar to, a prior art compound even though a particular benefit of the claimed compound asserted by patentee is not expressly disclosed in the prior art. If the prior art compound does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, Applicant’s recognition of the benefit is not in itself sufficient to distinguish the claimed compound from the prior art. In re Dillon, 919 F.2d 688, 693, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc). In the instant case, the exemplary immunotherapeutic VXM01 cancer vaccine agent species and the exemplary therapeutic anti-PD-1 antibody agent species expressly named and disclosed in the prior art fall within the species recited in the instant claims and therefore, these expressly named species are expected to have the same anti-tumor beneficial characteristics or effects as the instantly recited species. The therapeutic antitumor effects as well as the lesional tumor regression effects of Brahmer’s anti-PD-1 antibody checkpoint inhibitor and the VXM01’s anti-angiogenic activity and the anti-tumor activity shown in different tumor types are intrinsic to and inseparable from the prior art VXM01.
In sum, given the express teachings of the administration of an anti-PD-1 antibody checkpoint inhibitor therapeutic agent and the administration of the immunotherapeutic Vaximm Gmbh’s VXM01 cancer vaccine agent comprising the VEGFR-2-encoding S. typhi Ty21a in a method of treatment of any type of cancer as taught by Bender, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have both the art-known administration of an art-known therapeutic anti-PD-1 antibody checkpoint inhibitor having the demonstrated tumor-regressing antitumor activity as taught by Brahmer et al. and the art-known administration of the Vaximm Gmbh’s VEGFR-2-encoding Ty21a VXM01 cancer vaccine having the demonstrated anti-angiogenic activity and the intrinsic anti-tumor activity (as evidenced by Schmitz-Winnenthal et al., March 2013), which treated cancer as taught by Schmitz-Winnenthal et al. (March 2015), advantageously in a single method of treatment of human solid tumors to arrive at the instant invention. One of ordinary skill in the art would have been motivated to produce the instant invention for the expected benefit of providing enhanced or additional anti-cancer therapeutic effects advantageously via a single method of treatment. Given that PD-L1 is intrinsically and extensively expressed in cancer cells, Brahmer’s art-known anti-PD-1 antibody is expected to be efficacious in the resultant single method of cancer treatment in addition to the anti-angiogenic and the anti-tumor therapeutic effects of Schmitz-Winnenthal’s (2015) or Bender’s VXM01. As set forth previously, it is prima facie obvious to combine two elements or steps each of which is taught by the prior art to be useful for the same purpose, i.e., anti-cancer therapeutic purpose, in order to form a third product or method 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.’ See MPEP 2144.06. In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Since the recited elements were known in the prior art and administering said elements in a method to treat cancer was also known in the art, one of ordinary skill in the art would have beneficially administered them in a single method to accomplish the same purpose of treating a human solid tumor via induction of enhanced anticancer effects, reduction of the growth and size of the tumor, and shrinkage of the tumor. In KSR v. Teleflex, 550 U.S. (2007), the Supreme Court decided that when elements, techniques, items, or devices are combined, united, or arranged, and when, in combination, each item performs the function it was designed to perform, the resulting combination --something the court called ‘ordinary innovation’-- is not patentable. This can be true even if there is no teaching, suggestion, or motivation to make the combination. KSR International Co. v. Teleflex Inc.,127 S. Ct. 1727, 1741 (2007) also discloses that ‘[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results’. None of Figures 23-25 in the as-filed specification demonstrate the asserted synergistic effect of VXM01 in combination with an anti-PD-1 antibody. To establish obviousness, it is not necessary that the motivation come explicitly from the reference itself. The natural presumption that two individually art-known agents and their art-known administrations are beneficial in a method of cancer treatment and would provide a third method also useful for treatment of cancer flows logically from each having been individually taught in the prior art. It should be noted that what would reasonably have been known and used by one of ordinary skill in the art need not be explicitly taught. See In re Nilssen, 851 F.2d 1401, 7 USPQ2d 1500 (Fed. Cir. 1988). In the instant case, the teachings expressly and impliedly taught in the cited references provide sufficient reason, suggestion, or motivation to combine their teachings. The test of obviousness is not express suggestion of the claimed invention in any and all of the references, but rather what the references taken collectively would reasonably have suggested to those of ordinary skill in the art presumed to be familiar with them. In re Keller, 642 F.2d 413, 425, 208 USPQ 871, 881 (CCPA 1981). Obviousness does not require absolute predictability (see In re Lamberti, 192 USPQ 278), but only a reasonable expectation of success (see In re O’Farrell, 7 USPQ 2d 1673, Fed. Cir. 1988). The rejection stands.
Double Patenting Rejection(s) Maintained
15) The provisional rejection of claims 1, 4, 5, 7, 8, 10, 12 and 20-22 set forth at paragraph 27 of the Office Action mailed 06/03/24 and at paragraph 32 of the Office Action mailed 12/26/24 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 12, 13, 14, 16-18, 5, 4 and 1 of the co-pending application 17273590 application in view of Brahmer et al. (J. Clin. Oncol. 28: 3167-3175, 2010, of record) (Brahmer et al., 2010) is maintained.
Applicant contends that the pending claims of the ‘590 application are directed to five or more neoantigens in combination with a checkpoint inhibitory antibody against PD-1/PD-L1 rather than method of treating cancer comprising the use of a Salmonella-based vaccine encoding VEGFR-2 with a checkpoint inhibitory antibody against PD-1/PD-L1.
Applicant’s argument has been considered, but is not persuasive. Contrary to Applicant’s assertion, the treatment method of the identified claims of the co-pending ‘590 application including claims 12 and 5 comprises administering S. typhi Ty21a encoding VEGFR-2 and an antibody against PD-1.
Applicant further submits the following:
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However, the relevance of Applicant’s statement supra to the instant rejection set forth over the co-pending 17273590 application is not understood.
16) The rejection of claims 1, 4, 5, 7, 8, 10, 12 and 20-22 set forth in paragraph 40 of the Office Action mailed 12/26/24 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-18 of US patent 10293037 B2 (of record) and Brahmer et al. (J. Clin. Oncol. 28:3167-3175, 2010, of record) in view of Bender (US 20140248211 A1, of record) is maintained.
Applicant contends that the claims of the ‘037 are directed to a method of providing cancer treatment comprising orally administering to a patient VXM01 DNA vaccine, wherein a single dose comprises 106 to 109 CFU. Applicant states that the claims of the ‘037 patent do not disclose VXM01 in a combination with a checkpoint inhibitor, particularly antibodies that block the PD-1/PD-L1 interaction. Applicant refers to section V of his/her response and states
that neither Brahmer et al. nor Bender teaches or suggests each and every limitation of claim 1, specifically, a person of ordinary skill in the art would further know that the addition of an anti-PD-1 antibody without PD-L1 expression would not have provided a beneficial effect for the patient. Applicant submits that this information was only present based on the finding of an increased expression of PD-L1 upon VXM01 vaccination demonstrated in the instant application, not on the basis of the facts gleaned from the prior art. Applicant states that if the obviousness rejection outlined in Section V is overcome, this double patenting rejection should also be overcome and that the rejection should be withdrawn.
Applicant’s arguments have been considered, but are not persuasive. The claims of the ‘037 patent do not disclose a method wherein a single dose of VXM01 comprises ‘106 to 109’ CFU. Instant claim 1, as amended, does not have a ‘single dose’ requirement. As set forth previously, instant claims are prima facie obvious over the claims of the ‘868 patent in view of Brahmer et al. and Bender based on the facts gleaned from the prior art. As set forth supra in this Office Action, the 35 U.S.C § 103 obviousness rejection is maintained and so also this double patenting rejection as it still applies to instant claims as amended. Applicant is referred to the Office’s obviousness rationale provided in this Office Action and the Office’s rebuttal of Applicant’s arguments with regard to Brahmer et al. and Bender.
17) The rejection of claims 1, 4, 5, 7, 8, 10, 12 and 20-22 set forth in paragraph 41 of the Office Action mailed 12/26/24 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-14 of US patent 9415098 B2 (of record) and Brahmer et al. (J. Clin. Oncol. 28:3167-3175, 2010, of record) in view of Bender (US 20140248211 A1, of record) is maintained.
Applicant contends that the claims of the ‘098 are directed to a method of providing cancer treatment comprising orally administering to a patient VXM01 DNA vaccine, wherein a single dose comprises 106 to 109 CFU. Applicant states that the claims of the ‘098 patent do not disclose VXM01 in a combination with a checkpoint inhibitor, particularly antibodies that block the PD-1/PD-L1 interaction. Applicant refers to section V of his/her response and states that neither Brahmer et al. nor Bender teaches or suggests each and every limitation of claim 1, specifically, a person of ordinary skill in the art would further know that the addition of an anti-PD-1 antibody without PD- L1 expression would not have provided a beneficial effect for the patient. Applicant asserts that this information was only present based on the finding of an increased expression of PD-L1 upon VXM01 vaccination demonstrated in the instant application, not on the basis of the facts gleaned from the prior art. Applicant states that if the obviousness rejection outlined in Section V is overcome, this double patenting rejection should also be overcome and that the rejection should be withdrawn.
Applicant’s arguments have been considered, but are not persuasive. As set forth previously, instant claims are prima facie obvious over the claims of the ‘098 patent in view of Brahmer et al. and Bender based on the facts gleaned from the prior art. As set forth supra in this Office Action, the 35 U.S.C § 103 obviousness rejection is maintained and so also this double patenting rejection as it still applies to instant claims as amended. Applicant is referred to the Office’s obviousness rationale provided in this Office Action and the Office’s rebuttal of Applicant’s arguments with regard to Brahmer et al. and Bender.
18) The rejection of claims 1, 4, 5, 7, 8, 10, 12 and 20-22 set forth in paragraph 42 of the Office Action mailed 12/26/24 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 1-21 of US patent 10980868 B2 (of record) and Brahmer et al. (J. Clin. Oncol. 28:3167-3175, 2010, of record) in view of Bender (US 20140248211 A1, of record) is maintained.
Applicant contends that the claims of the ‘868 are directed to a method of providing cancer treatment comprising orally administering to a Salmonella-based vaccine encoding VEGFR-2 to a patient, wherein a single dose comprises 106 to 109 CFU. Applicant asserts that the claims of the ‘868 patent do not disclose a Salmonella-based vaccine encoding VEGFR-2 in a combination with a checkpoint inhibitor, particularly antibodies that block the PD-1/PD-L1 interaction. Applicant refers to section V of his/her response and states that neither Brahmer et al. nor Bender teaches or suggests each and every limitation of claim 1, specifically a person of ordinary skill in the art would further know that the addition of an anti-PD-1 antibody without PD-L1 expression would not have provided a beneficial effect for the patient. Applicant asserts that this information was only present based on the finding of an increased expression of PD-L1 upon VXM01 vaccination demonstrated in the instant application, not on the basis of the facts gleaned from the prior art. Applicant states that if the obviousness rejection outlined in Section V is overcome, this double patenting rejection should also be overcome and that the rejection should be withdrawn.
Applicant’s arguments have been considered, but are not persuasive. As set forth previously, instant claims are prima facie obvious over the claims of the ‘868 patent in view of Brahmer et al. and Bender based on the facts gleaned from the prior art. As set forth supra in this Office Action, the 35 U.S.C § 103 obviousness rejection is maintained and so also this double patenting rejection as it still applies to instant claims as amended. Applicant is referred to the Office’s obviousness rationale provided in this Office Action and the Office’s rebuttal of Applicant’s arguments with regard to Brahmer et al. and Bender.
19) The rejection of claims 1, 4, 5, 7, 8, 10, 12 (not 11 as mistyped inadvertently) and 20-22 set forth in paragraph 43 of the Office Action mailed 12/26/24 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 12, 11, 4, 3, 1, 14, 7-9, 6 and 5 of US patent 10815455 B2 (of record) in view of Brahmer et al. (J. Clin. Oncol. 28: 3167-3175, 2010, of record) and Bender (US 20140248211 A1, of record) is maintained.
Applicant contends that the claims of the ‘455 patent do not disclose a Salmonella-based vaccine encoding VEGFR- 2 in a combination with a checkpoint inhibitor, particularly antibodies that block the PD-1/PD-L1 interaction. Applicant refers to section V of his/her response and states that neither Brahmer et al. nor Bender teaches or suggests each and every limitation of claim 1, specifically a person of ordinary skill in the art would further know that the addition of an anti-PD-1 antibody without PD-L1 expression would not have provided a beneficial effect for the patient. Applicant asserts that this information was only present based on the finding of an increased expression of PD-L1 upon VXM01 vaccination demonstrated in the instant application, not on the basis of the facts gleaned from the prior art. Applicant states that if the obviousness rejection outlined in Section V is overcome, this double patenting rejection should also be overcome and that the rejection should be withdrawn.
Applicant’s arguments have been considered, but are not persuasive. As set forth previously, instant claims are prima facie obvious over the claims of the ‘455 patent in view of Brahmer et al. and Bender based on the facts gleaned from the prior art. As set forth supra in this Office Action, the 35 U.S.C § 103 obviousness rejection is maintained and so also this double patenting rejection as it still applies to instant claims as amended. Applicant is referred to the Office’s obviousness rationale provided in this Office Action and the Office’s rebuttal of Applicant’s arguments with regard to Brahmer et al. and Bender.
Double Patenting Rejection(s)
20) Claims 1, 4, 5, 7, 8, 10, 12 and 20-22 are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 11, 3, 2, 1, 14, 7-9, 6, 5 and 12 of US patent 10441645 B2 (of record).
Although the claims are not identical, they are not patentably distinct from each other. The identified claims of the ‘645 patent, depend directly or indirectly from claim 1 and therefore include all the features of the method claim(s) they depend upon. Claim 11 of the ‘645 patent, set forth below, teaches a method for treating a cancer in a patient comprising administering one or more further attenuated mutant Salmonella typhi Ty21a comprising at least one copy of a DNA molecule comprising a eukaryotic expression cassette encoding human VEGFR-2, i.e., the instantly recited SEQ ID NO: 1.
11. The method of claim 3, wherein said one or more further strain(s) of Salmonella typhi Ty21a comprise(s) a strain of Salmonella typhi Ty21 encoding human VEGFR-2.
Claim 5 of the ‘645 patent teaches that the S. typhi 21a is administered in combination with a checkpoint inhibitor antibody. Claim 12 of the ‘645 patent teaches that the S. typhi 21a is administered before or during the administration of the checkpoint inhibitor antibody. Claim 4 of the ‘645 patent teaches that the one or more further attenuated strains of Salmonella typhi 21a are co-administered with the attenuated mutant strain of Salmonella typhi 21a. Claim 6 of the ‘645 patent teaches that the attenuated mutant Salmonella typhi Ty21a is administered orally. Claim 7 of the ‘645 patent identifies the solid tumor treated by the method as pancreatic cancers. Claim 8 of the ‘645 patent teaches that a single dose comprises from about 106 to 109 CFU of the Salmonella typhi Ty21a. Claim 5 teaches that the method further comprises chemotherapy. Claim 2 of the ‘645 patent teaches that the attenuated mutant Salmonella typhi Ty21a comprises the kanamycin antibiotic resistance gene, a pMB1 ori and a CMV promoter. As in In re Basell Pollolefine Italia S.P.A., 89 USPQ2d 1030, 1036 (Fed. Cir. 2008), the specification of the ‘645 patent at lines 20-23 of column 10 that defines the checkpoint inhibitor antibodies expressly includes anti-PD1 indicating that anti-PD1 antibody was intended to fall within the meaning and coverage of the claims. As also in In re Basell Pollolefine Italia S.P.A., 89 USPQ2d 1030, 1036 (Fed. Cir. 2008), the specification of the ‘645 patent (for example, at lines 38-39 of column 11) describes that the administration includes multiple administration indicating that multiple administrations of the Ty21a was intended to fall within the meaning and coverage of the claims. Note that ‘[The specification] may be used to learn the meaning of terms and in interpreting the coverage of a claim’ [Emphasis added]. In re Basell Pollolefine Italia S.P.A., 89 USPQ2d 1030, 1036 (Fed. Cir. 2008). Instant claims are anticipated by the identified claims of the ‘645 patent.
Conclusion
21) No claims are allowed.
Correspondence
22) Any inquiry concerning this communication or earlier communications from the Examiner should be directed to S. Devi, Ph.D., whose telephone number is (571) 272-0854. A message may be left on the Examiner’s voice mail system. The Examiner is on a flexible work schedule, however she can normally be reached Monday to Friday from 7.00 a.m. to 4.00 p.m. (EST). If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's Supervisor, Gary Nickol, can be reached at (571) 272-0835. The fax phone number for the organization where this application or proceeding is assigned (571) 273-8300.
23) Information regarding the status of an application may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center or Private PAIR to authorized users only. Should you have questions about access to Patent Center or the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
/S. DEVI/
S. Devi, Ph.D.Primary Examiner
Art Unit 1645
September, 2025
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