DETAILED ACTION
Applicant’s amendment and response received on 11/14/25 has been entered. Claim 8 has been canceled. Claims 1-7, 9, 13, 32, 35-36, 43, 48-49, 52 and 72-74 are pending and currently under examination based on the elected species of DAMP-HMGB1 and CRT as the species of DAMP, and the elected species of tumor cell line-malignant melanoma. 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 . Those sections of Title 35, US code, not included in this action can be found in a previous office action.
Claim Rejections - 35 USC § 112
The rejection of claims 2, 6-7, 9, 13, and 36 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in view of applicant’s amendments to the claims.
Claim Rejections - 35 USC § 103
Amended claims 1-7, 9, 13, 32, 35-36, 43, 48-49, 52, and 72-74 remain or are newly rejected under 35 U.S.C. 103 as being unpatentable over Aguilera et al. (2011) Clin. Cancer Res., Vol. 17(8), 2474-2483, in view of Multhoff et al. (1995) Int. J. Cancer, Vol. 61, 272-279, Kim et al. (2006) Immunol. Lett., V. 103, 142-148, and Sondak et al. (2003) Sem.Canc.Biol., Vol. 13, 409-415. Note that claim 13 has been added to this rejection based on the amendment to the claim which now recites that the adjuvant is selected from a list which included a glycosylated adjuvant. Applicant’s amendment 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.
The applicant provides arguments individually for each cited reference and argues that there are crucial differences between Aguilera et al. and the claimed invention. According to applicant, Aguilera teaches a different method of use for the heat-shock-conditioned tumor lysates than that taught by applicant. The applicant argues that Aguilera teaches to use the lysates to activate peripheral monocytes ex vivo and not as a vaccine formulation for direct administration. The applicant also argues that Aguilera does not control cell viability greater than 80% before lysis, does not standardize the sources or the tumor cell line antigens, and does not teach to combine the lysates with natural adjuvants. The applicant states that LycellVax, as taught by applicant, establishes standardized combinations of heat-shock-conditioned lysates from distinct melanoma, gallbladder, and colorectal tumor lineages and that this formulation in combination with specific natural adjuvants elicits immunogenic and therapeutic effects in vivo. The applicant then argues that Multhoff also fails to teach or suggest the claimed invention, arguing that Multhoff only teaches the presence of HSP72 on tumor-cell surfaces after heat stress and did not create any lysate formulations or vaccines as claimed. The applicant argues that the technical integration of the LycellVax led to superior in vivo immunogenicity. In addition, the applicant argues that Multhoff did not quantify post-treatment viability or teach to maintain the viable cells for vaccine preparation. Turning to Kim et al. and Sondak et al., the applicant argues that Kim et al. used destructive freezing for cell lysis and Sondak et al. utilized mechanical disruption to generate non-heat conditioned tumor lysates. Finally, the applicant argues that none of the references alone or in combination teach the unpredictable biological outcomes demonstrated by Figures 6-13 where only certain lysate adjuvant combinations provoked immunity and produced a synergistic effect.
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). Further, 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). 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 is noted that there are three different types of claims in the claim set under examination. Claims 1-7, 9, 13, 32, 35-36, 43 are product claims drawn to a immunogenic composition. Claims 48-49, and 52 are methods of making the product which is an immunogenic composition, and clams 72-74 are methods of treating cancer comprising administering the immunogenic composition.
In the instant rejection, Aguilera et al. teaches the generation of an immunogenic composition comprising a heat-shocked allogeneic melanoma cell lysate referred to as TRIMEL which is capable of stimulating dendritic cells useful for inducing CD8+ anti-melanoma T cell responses in vitro and in vivo (Aguilera et al., abstract). Specifically, Aguilera et al. teaches that TRIMEL is a cell lysate derived from 3 allogeneic malignant melanoma cells lines- Mel1, Mel2, and Mel3- using a multi-step process where 1) each cell line is heat shock-treated at 42oC for 1 hr followed by incubation for 2 hours at 37oC, 2) the heat-shocked cell lines are mixed in equal amounts and lysed through repeated freeze-thaw cycles, and 3) the cell lysate obtained is sonicated and irradiated (Aguilera et al., page 2475). Aguilera et al. further teaches that the melanoma cell lines used to generate TRIMEL expressed a number of melanoma associated antigens including MART-1, gp100, tyrosinase, NY-ESO1, MAGE1, MAGE3, MC1R, MCSP, survivin, and Her2/neu (Aguilera et al., page 2476). In addition, Aguilera et al. reports that heat shock of the TRIMEL melanoma cell lines increased HMGB1 and CRT levels, and induced the expression of IFN-y, TNF-a, IL-10, and IL-6 by dendritic cells exposed to TRIMEL (Aguilera et al., pages 2475-2476, and 2478-2479). The applicant argues that Aguilera teaches a different methods of using the lysate, and does not teach the particular components of the LycellVax composition disclosed in applicant’s working examples. In response, as noted above, claims 1-7, 9, 13, 32, 35-36, 43 are product claims drawn to a immunogenic composition. The claims as written are not limited to a “standardized combination” of heat-shock-conditioned lysates from distinct melanoma, gallbladder, and colorectal tumor lineages as applicant argues are present in LycellVax, nor do the claims, with the exception of claims 6-7, limit the adjuvant to an natural adjuvant. Similarly, the claims directed to methods of making the immunogenic composition and the methods of administering the composition in vivo do not recite these limitations. Likewise, the immunogenic composition is not limited to lysate made using any particular methodology as long as the cells exhibit the claimed viability, and the methods of making the immunogenic composition do not recite any specific steps regarding the heat shock incubation step. All that is required is maintaining the viability of the heat treated cells prior to lysis to greater than 80% viability. Thus, applicant’s arguments regarding specific aspects of the LycellVax formulation and method of preparing the specific LycellVax formulation are largely based on limitations which are not present in any of the currently pending product or method claims.
In addition, the teachings of Aguilera et al. are not read in a vacuum, the rejection is based on the combined teachings and motivation provided by all four cited references, Aguilera et al., Multhoff et al., Kim et al., and Sondak et al. As noted above, there is no requirement that any one reference provide the teaching and motivation for all structural or functional elements of a claim. The rejection of record acknowledged that while Aguilera et al. teaches a method of making the TRIMEL lysate where the 3 melanoma cell lines are subjected to 1 hr heat shock at 42oC followed by 2 hrs at 37oC, which is incidentally the exact same method disclosed in the specification, Aguilera et al. does not report on the cell viability of the cells following heat shock. Further, Aguilera et al., while disclosing that the heat shocked proteins have increased levels of DAMP molecules including increased HMGB1 and CRT levels, Aguilera et al. does not specifically teach an increase in a third DAMP molecule. Multhoff et al. supplements Aguilera et al. by teaching that heat shock of tumors cells induces the expression of various heat-shock proteins (HSP), particularly the heat-shock proteins HSP72 and HSP73, which can increase the immunogenicity of tumor cells (Multhoff et al., pages 272 and 279). Multhoff et al. also reports on the effects of heat shock treatment at various temperatures and for various times on cell viability. Specifically, Multhoff et al. tested cultures of sarcoma cell line (ES) cells which had been exposed to 41.8oC, 42oC, 43oC, 44oC, and 45oC for 0-450 minutes followed by culture at 37oC for 12 days using a clonogenic cell survival assay, and dye exclusion assays, both Trypan blue and propidium iodide (Multhoff et al., page 273). Contrary to applicant’s arguments, Multhoff specifically teaches that culture at 41.8oC for up to 450 min was essentially non-lethal for the tumor cells with greater than 97% cell viability as measure by the clonogenic survival assay, and greater than 98% cell viability as measured by Trypan blue and propidium iodide exclusion assay (Multhoff et al., page 273). Figure 1 of Multhoff et al. further shows that heat shock at 42oC for 60 min has minimal effect on cell viability (Multhoff et al., Figure 1, page 273). Multhoff et al. also teaches that temperatures greater than 42oC markedly reduced the viability of the tumor cells (Multhoff et al., page 274, see also Figure 1). Finally, Multhoff et al. teaches that similar results were obtained with other tumor types (Multhoff et al., page 273). Thus, Multhoff et al. clearly demonstrates that a 1 hr heat shock of tumor cells at either 41.8oC or at 42oC results in a cell viability of over 80%, and further demonstrates that heat shock of tumor cells increases expression of the DAMP molecule HSP72. Thus, Multhoff et al. provides evidence that practice of the heat shock protocol of Aguilera et al. will result in a pre-lysis heat-shock conditioned melanoma cell population that is over 80% viable, and which, based on the combined teachings of Aguilera et al. and Multhoff et al., would further have elevated levels of at least three DAMP molecules including HMGB1, CRT, and HSP72. As such, based on the teachings and evidence provided by Multhoff et al., it would have been prima facie obvious to the skilled artisan to produce the heat-shocked 3 melanoma cell line lysate according to Aguilera et al. where the heat shock involves incubation of the melanoma cells at either 41.8oC or at 42oC for 1 hr followed by incubation at 37oC with a reasonable expectation that the heat-shocked cell populations post-heat shock and prior to lysis would be at least 80% viable and would express increased level of the three DAMP molecules HMGB1, CRT, and HSP72.
The rejection also noted that Aguilera et al., while teaching the immunogenic TRIMEL lysate formulation, does not teach to further combine the lysate formulation with an adjuvant. Kim et al. was cited to supplement Aguilera et al. by teaching an immunogenic composition comprising a heat-shock tumor lysate and an adjuvant which is Keyhole Limpet hemocyanin (KLH) an natural adjuvant derived from a gastropod mollusk of the family Fissurellidae, where the heat-shock tumor lysate is generated by incubating a pancreatic tumor cell line, PANC02, at 42oC for 2 hrs, followed by culture of the cells at 37oC for 24 hours, followed by several freeze/thaw cycles and size exclusion centrifugation/filtration (Kim et al., page 143). The applicant disparages this method since it uses freeze/thaw to lyse the cells, however there are no limitations in the claims that preclude freeze/thaw lysis. Further, Kim et al. teaches that the tumor lysate is then mixed with KLH, where the concentration of KLH is 50 ug/ml (Kim et al., page 143). Kim et al. provides motivation for combining a heat-shock tumor lysate with KLH adjuvant by teaching that adjuvants such as the "highly immunogenic" KLH augment antigen-specific CTLs and are beneficial in shifting T cell responses towards a Th1 response (Kim et al., page 147). Therefore, in view of the motivation provided by Kim et al. for combining a heat-shock lysate immunogenic formulation with an adjuvant such as KLH, and in particular at a concentration of 50ug/ml, it would have been prima facie obvious to the skilled artisan at the time of filing to combine the heat shocked triple melanoma cell line lysate immunogenic composition taught by Aguilera et al. in view of Multhoff et al. with KLH with a reasonable expectation of producing an immunogenic formulation with enhanced immunogenic properties.
While Aguilera et al. in view of Multhoff et al. and Kim et al. provide the teachings and motivation for an immunogenic composition as claimed comprising a heat shocked triple melanoma cell line tumor lysate and KLH adjuvant, the rejection of record acknowledged that neither Aguilera et al. nor Kim et al. specifically teaches to directly administer the heat shocked tumor lysate and KLH in vivo for treating cancer. Sondak et al. supplements Aguilera et al., Multhoff et al., and Kim et al. by teaching a method of treating melanoma by administering a tumor lysate vaccine comprised of lysates from two allogeneic melanoma cell lines and an adjuvant, where the adjuvant comprises two bacterial adjuvants (DETOX), and which has been trademarked as Melacine® (Sondak et al., page 410). Sondak et al. reports the results of several clinical trails where Melacine was administered to Stage III and/or IV patients either alone or in combination with IFN-alpha, where a positive therapeutic response was observed (Sondak et al., pages 411-414). Sondak et al. further teaches that the melanoma lysate comprises at least gp100, tyrosinase, TRP-1, MART-1, MAGE1, MAGE2, and MAGE3 (Sondak et al., page 412). While Sondak et al., as argued by applicant, did test a non-heat-shocked combination of two melanoma cell lines lysates and an adjuvant, Aguilera et al. and Kim et al. have already provided the teachings that heat shock of the melanoma cell lines prior to lysis provides several advantages. In particular, Aguilera et al. teaches that heat shock of tumor cells prior to lysis induces DAMPs which trigger fast monocyte activation to mature dendritic cells and further are responsible for efficient antigen cross-presentation useful for mediating an optimal immune response in vaccinated patients (Aguilera et al., page 2475). Kim et al. describes a synergistic effect of combining tumor lysate comprising tumor antigens and heat shock proteins through heat treatment of tumor cells prior to lysis, and demonstrates that heat-shocked tumor lysate exhibits increased T cell activation, increased expansion of IFN-y secreting T cells and increased cytotoxicity of T cells compared to non-heat-shocked tumor lysate (Kim et al., abstract and page 143). Thus, based on the motivation provided by Sondak et al. to directly administer a melanoma tumor lysate formulation in combination with an adjuvant for cancer therapy of melanoma, and the teaching and motivation provided by Aguilera et al. and Kim et al. for using a heat-shocked tumor lysate over non-heat-shocked tumor lysate, it would have been prima facie obvious to the skilled artisan at the time of filing to administer the heat-shocked tumor lysate taught by Aguilera et al. in view of Multhoff and an adjuvant such as KLH or DETOX as taught by Kim et al. and Sondak et al. to a patient with melanoma with a reasonable expectation of success of treating the melanoma.
Finally, in regards to several statements made by applicant regarding unpredictable results and unexpected synergy obtained using the LyCellVax immunogenic composition and a natural adjuvant, it is reiterated that the claims under examination are not limited to the LyCellVax composition in combination with specific natural adjuvant. The applicant is also reminded that any alleged evidence of unexpected results must be commensurate in scope with the claimed invention. and that a greater, or greater than additive, effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected MPEP 716.02 (a) and (d). Further, the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP 716.01(c) for examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration. A particular example of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results. MPEP 716.01(c). Furthermore, note that "[a]lthough secondary considerations must be taken into account, they do not necessarily control the obviousness conclusion." Pfizer, Inc. V. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir. 2007) ("[E]ven if [the patentee] showed that [the invention] exhibits unexpectedly superior results, this secondary consideration does not overcome the strong showing of obviousness in this case."). For example, "[t]o be particularly probative, evidence of unexpected results must establish that there is a difference between the results obtained and those of the closest prior art, and that the difference would not have been expected by one of ordinary skill in the art at the time of the invention." Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014).
Thus, for the reasons set forth above, applicant’s argument have not been found persuasive and the rejection stands.
Amended claims 1-4, 32, 35-36, 43, 48-49, and 52 remain rejected under 35 U.S.C. 103 as being unpatentable over Aguilera et al. (2011) Clin. Cancer Res., Vol. 17(8), 2474-2483, in view of Multhoff et al. (1995) Int. J. Cancer, Vol. 61, 272-279, Liu et al. (2015) Acta Pharm., Vol. 65, 105-116, and US Patent Application Publication 2017/0189523 (2017), Stegmann et al.. The rejection of claim 13, previously rejected, has been withdrawn in view of the amendments to claim 13 which is now drawn to the use of an adjuvant which is not a virosome. Applicant’s amendment 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.
The applicant argues that the rejection has been rendered moot by the amendment to claim 13 which is now drawn to the use of an adjuvant which is not a virosome. The applicant further argues that the cited references in combination do not suggest the problems addressed by the claims and do not suggest a solution similar to that of the claims. The applicant also argues that the references are unrelated because the configuration defined in the claims is much more precise that the generic functional differences articulated in the rejection. Finally, the applicant asserts that impermissible hindsight has been used to combine the teachings of the disparate references.
In response, while claim 13 has been amended to recite adjuvants which are not a virosome, and therefore has been removed from this rejection, claims 1-4, 32, 35-36, 43, 48-49, and 52 continue to broadly encompass the use of any adjuvant, including a virosome. Therefore, applicant’s amendment to claim 13 does not overcome the rejection of claims 1-4, 32, 35-36, 43, 48-49, and 52.
In addition, regarding applicant’s assertion of improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In addition, 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 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). 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).
As to the particulars of the LycellVax composition and the pairing of the LycellVax and a natural adjuvant, as noted above, claims 1-7, 9, 13, 32, 35-36, 43 are product claims drawn to a immunogenic composition. The claims as written are not limited to a “standardized combination” of heat-shock-conditioned lysates from distinct melanoma, gallbladder, and colorectal tumor lineages as applicant argues are present in LycellVax, nor do the claims, with the exception of claims 6-7, limit the adjuvant to an natural adjuvant. Similarly, the claims directed to methods of making the immunogenic composition and the methods of administering the composition in vivo do not recite these limitations. Likewise, the immunogenic composition is not limited to lysate made using any particular methodology as long as the cells exhibit the claimed viability, and the methods of making the immunogenic composition do not recite any specific steps regarding the heat shock incubation step. All that is required is maintaining the viability of the heat treated cells prior to lysis to greater than 80% viability. Thus, applicant’s arguments regarding specific aspects of the LycellVax formulation and method of preparing the specific LycellVax formulation are largely based on limitations which are not present in any of the currently pending product or method claims.
As set forth in the rejection of record, Aguilera et al. teaches the generation of an immunogenic composition comprising a heat-shocked allogeneic melanoma cell lysate referred to as TRIMEL which is capable of stimulating dendritic cells useful for inducing CD8+ anti-melanoma T cell responses in vitro and in vivo (Aguilera et al., abstract). Specifically, Aguilera et al. teaches that TRIMEL is a cell lysate derived from 3 allogeneic melanoma cells lines- Mel1, Mel2, and Mel3 using a multi-step process where 1) each cell line is heat shock-treated at 42oC for 1 hr followed by incubation for 2 hours at 37oC, 2) the heat-shocked cell lines are mixed in equal amounts and lysed through repeated freeze-thaw cycles, and 3) the cell lysate obtained is sonicated and irradiated (Aguilera et al., page 2475). Aguilera et al. further teaches that the melanoma cell lines used to generate TRIMEL expressed a number of melanoma associated antigens including MART-1, gp100, tyrosinase, NY-ESO1, MAGE1, MAGE3, MC1R, MCSP, survivin, and Her2/neu (Aguilera et al., page 2476). In addition, Aguilera et al. reports that heat shock of the TRIMEL melanoma cell lines increased HMGB1 and CRT levels, and induced the expression of IFN-y, TNF-a, IL-10, and IL-6 by dendritic cells exposed to TRIMEL (Aguilera et al., pages 2475-2476, and 2478-2479).
While Aguilera et al. teaches a method of making the TRIMEL lysate where the 3 melanoma cell lines are subjected to 1 hr heat shock at 42oC followed by 2 hrs at 37oC, which is incidentally the exact same method disclosed in the specification, Aguilera et al. does not report on the cell viability of the cells following heat shock. Further, Aguilera et al., while disclosing that the heat shocked proteins have increased levels of DAMP molecules including increased HMGB1 and CRT levels, Aguilera et al. does not specifically teach an increase in a third DAMP molecule. Multhoff et al. supplements Aguilera et al. by teaching that heat shock of tumors cells induces the expression of various heat-shock proteins (HSP), particularly the heat-shock proteins HSP72 and HSP73, which can increase the immunogenicity of tumor cells (Multhoff et al., pages 272 and 279). Multhoff et al. also reports on the effects of heat shock treatment at various temperatures and for various times on cell viability. Specifically, Multhoff et al. tested cultures of sarcoma cell line (ES) cells which had been exposed to 41.8oC, 42oC, 43oC, 44oC, and 45oC for 0-450 minutes followed by culture at 37oC for 12 days using a clonogenic cell survival assay, and dye exclusion assays, both Trypan blue and propidium iodide (Multhoff et al., page 273). Multhoff teaches that culture at 41.8oC for up to 450 min was essentially non-lethal for the tumor cells with greater than 97% cell viability as measure by the clonogenic survival assay, and greater than 98% cell viability as measured by Trypan blue and propidium iodide exclusion assay (Multhoff et al., page 273). Figure 1 of Multhoff et al. further shows that heat shock at 42oC for 60 min has minimal effect on cell viability (Multhoff et al., Figure 1, page 273). Multhoff et al. also teaches that temperatures greater than 42oC markedly reduced the viability of the tumor cells (Multhoff et al., page 274, see also Figure 1). Finally, Multhoff et al. teaches that similar results were obtained with other tumor types (Multhoff et al., page 273). Thus, Multhoff et al. clearly demonstrates that a 1 hr heat shock of tumor cells at either 41.8oC or at 42oC results in a cell viability of over 80%, and further demonstrates that heat shock of tumor cells increases expression of the DAMP molecule HSP72. Thus, Multhoff et al. provides evidence that following the heat shock protocol of Aguilera et al. will result in a pre-lysis heat-shock conditioned melanoma cell line population that is over 80% viable, and which, based on the combined teachings of Aguilera et al. and Multhoff et al., would further have elevated levels of at least three DAMP molecules including HMGB1, CRT, and HSP72. As such, based on the teachings and evidence provided by Multhoff et al., it would have been prima facie obvious to the skilled artisan to produce the heat-shocked 3 melanoma cell line lysate according to Aguilera et al. where the heat shock involves incubation of the melanoma cells at either 41.8oC or at 42oC for 1 hr followed by incubation at 37oC with a reasonable expectation that the heat-shocked cell populations prior to lysis would be at least 80% viable and would express increased level of the three DAMP molecules HMGB1, CRT, and HSP72.
Aguilera et al., while teaching the immunogenic TRIMEL lysate formulation, does not teach to further combine the lysate formulation with an adjuvant. Liu et al. supplements Aguilera et al. by teaching that virosomes are ideal vehicles for delivering immunogenic substances to host bodies as they can act both as a delivery agent and as a highly effective immune adjuvant (Liu et al., page 109). In particular, Liu et al. teaches the use of virosomes for cancer therapy where the virosomes are formulated to contain multiple tumor antigens such as melanoma antigens for use in melanoma immunotherapy (Liu et al., page 110). Stegmann et al. teaches the generation and use of virosomes comprising at least one tumor antigen for cancer therapy, where the virosomes are administered at a dosage of 0.001 mg/kg to 7 mg/kg per day in an adult (Stegmann et al., paragraphs 52, 56, 64, and 66). Therefore, it is maintained that in view of the benefits of combining tumor antigen based vaccines with virosomes, which can act both as a delivery agent and a highly effective immune adjuvant, as taught by both Liu et al. and Stegmann et al., it would have been prima facie obvious to the skilled artisan at the time of filing to combine the heat-shock melanoma tumor lysate taught by Aguilera et al. in view of Multhoff et al. with an adjuvant which is a virosome, to form an immunogenic formulation useful for immunotherapy of melanoma with a reasonable expectation of success.
Thus, from the above analysis it is clear that the cited references are not disparate and unrelated references, and as such applicant’s arguments have not been found persuasive in overcoming the rejection of record.
No claims are 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 from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634