DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05/19/2026 has been entered.
Status of Claims
The amended claims filed 04/20/2026 are acknowledged and entered.
Claims 21-23, 28-30 and 37 have been amended
Claims 1-20 are cancelled.
Claims 38-40 have been added
Claims 21-40 are pending and examined on their merits.
Response to Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Claim Rejections - 35 USC § 112 maintained
Claims 21-37 and newly added claims 38-40 are rejected under 35 U.S.C. § 112 (a), or 35 U.S.C. § 112 (pre-AIA ) first paragraph, because the specification, while being enabling to treat a cancer that expresses and presents SEQ ID NO. 1 on its surface by administering SEQ ID NO. 1 to a subject having said cancer, or for methods of using SEQ ID NO. 1 as an adjuvant paired with a cancer antigen wherein both are administered to a subject having a cancer that expresses the cancer antigen, or for treating cancer in mice with SEQ ID NO. 1 administration intratumorally, or for treating a cancer in humans targeted and killed by human dendritic cells stimulated by SEQ ID NO. 1, does not reasonably provide enablement to treat a human cancer via administering only SEQ ID NO. 1 when the cancer does not express the same nor for similar methods using SEQ ID NO. 1 alone without a cancer antigen also used as immunogen in the method to treat a cancer, nor for treating any human cancer for which no data is presented from use of SEQ ID NO. 1-stimulated human dendritic cells. The specification does not enable the prevention of any cancer and any subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Applicant' s arguments have been fully considered and are not persuasive. Therefore, the rejections are maintained.
Applicant' s Arguments:
- (a) In the present specification, it was confirmed that poly6, the peptide of SEQ ID NO. 1, is not specific to colorectal cancer but exhibits non-specific immune-inducing ability across various cancer types. A statistically significant Tip-DC population was formed in the group stimulated by the said poly6 (see, e.g., Specification at 29 and Fig. 22). Therefore, poly6 induces a direct anticancer effect in vivo by inducing differentiation into Tip-DC (see, e.g., Specification at 29-30).
Furthermore, an anticancer effect was confirmed in T-cell-deficient balb/c nu/nu mice, confirming results that support the direct anticancer-inducing ability of Tip-DC by inducing an anticancer effect mediated by innate immune cells (see Specification at 30 and Fig. 26).
- (b) The preventative effect of the claimed invention is also demonstrated in Example 4.(4) in which the claimed peptide was injected to mice prior to cancer cell injection (see Specification at 27 and Fig. 14).
- (c) Moreover, the Federal Circuit held that "when experimentation on human subjects is inappropriate ... the enablement requirement may be met by animal tests or in vitro data." Edwards Lifesciences AG v. Corevalve, inc., 699 F.3d 1305 (Fed. Cir. 2012); see also Scott v. Finney, 34 F.3d 1058, 1063 (Fed. Cir. 1994) ("Testing for the full safety and effectiveness of a prosthetic device is more properly left to the Food and Drug Administration. Title 35 does not demand that such human testing occur within the confines of Patent and Trademark Office proceedings."). In line with this, the MPEP also states that enablement is satisfied when there is a "reasonable correlation" between in vitro/animal data and in vivo (human) activity. MPEP §2164.02. Moreover, "the initial burden is on the examiner to give reasons for the lack of enablement, the examiner must also give reasons for a conclusion of lack of correlation for an in vitro or in vivo animal model example." Here, the examiner has not explained why the testing in mice provides insufficient correlation to the claimed subjects when the specification provides proof that the claimed polypeptide demonstrates cytotoxicity in multiple cancer cell lines derived from multiple animals (i.e., mouse and human). The office action, therefore, fails to establish a prima facie case of lack of enablement and places a burden of proof that goes beyond what is required by the law.
Accordingly, Applicant respectfully requests reconsideration and withdrawal of this rejection.
Examiner's Response to Arguments Applicant's arguments have been carefully considered but are not found persuasive.
- (a) As discussed in detail in the previous office actions, the specification only enables the treatment of a few cancers (listed above) but not just any cancer as the amended claim 21 now, more broadly, reads. Regarding the interpretive “wherein” clauses recited in claims 21, 28 and 37 (“wherein the polypeptide activates dendritic cells and increases the expression of at least one selected from the group consisting of TNF-a and iNOS in dendritic cells”), the clause does not recite any additional active method steps but simply states a characterization or conclusion of the results of those steps.
- (b) As discussed in detail in the previous office actions and with regards to the prevention of cancer, the specification does not disclose sufficient guidance or objective evidence that such polypeptide would predictably prevent the formation of cancer cells. The applicant claims that the results of an experiment where the peptide was injected to mice prior to cancer cell injection demonstrate prevention but this experiment at most demonstrates treatment since the cancer cells have already been formed when injected, even if after the injection of the polypeptide, and thus these cells are treated and not “prevented”. The prevention of cancer, let alone the prevention of any cancer with a polypeptide, is highly unpredictable. The specification is devoid of any models or experimental analysis that reasonably suggests that the claimed method would predictably prevent the formation of tumors in a mammal. This, combined with the state of the art of preventing cancer, suggests that undue experimentation would be required to practice the invention as broadly claimed. Therefore, prevention as claimed in the application has not been enabled.
(c) With regards to the cases (" Edwards Lifesciences AG v. Corevalve, inc., 699 F.3d 1305 (Fed. Cir. 2012) and Scott v. Finney, 34 F.3d 1058, 1063 (Fed. Cir. 1994)), applicant has failed to explain why the experimentation on human subjects is “inappropriate” in the case of enabling any cancer treatment or prevention using a polypeptide. It seems these cases involved invasive medical devices so it is not completely surprising that the use of animal testing might be sufficient for enablement as long as the animal testing is comprehensive and the data shows enablement. This would not be the case for a therapeutic peptide for treatment or prevention of any cancer, where more extensive testing is needed to enable such claims. The data needs to support the claimed invention but the specification fails to provide information that would allow the skilled artisan to fully practice the instant invention as claimed without undue experimentation. The reasons why there is a lack of correlation for an in vitro or in vivo animal model and the claimed method of treatment and prevention of any cancer have been discussed in detail in previous actions and above. The applicant claims that the specification provides proof that the claimed polypeptide demonstrates cytotoxicity in multiple cancer cell lines derived from multiple animals, however cytotoxicity data is not sufficiently proof for treatment or prevention of any cancer. The specification is enabled for a method of treating mice (in vivo data, not tested in humans) injected with some tumor cells (such as colon cancer MC38, melanoma B16F10 and HBV W4P expressing NIH-3T3 cells), it does not reasonably provide enablement for a method of treating any cancer and/or preventing any cancer in any non-human animal model.
(d) The specification teaches on pages 23-24 that the peptide claimed poly6 increases Thus, logically, it would not be useful alone with just this mechanism to reduce growth of an NO-dependent cancer. By providing NO, it would support growth of such a tumor. On page 25, the adjuvanticity of poly6 (instant SEQ ID NO. 1) is confirmed through dendritic cells activation. Figure 6 is asserted to show direct killing of tumor cells by dendritic cells; however, it is not clear how the data were obtained before FACS analysis (i.e. from what sort of cell culture or in vivo experiment.
Though direct mechanisms of tumor cell killing by dendritic cells have been noted in the prior art. These effects must be intratumoral. Wesa (Cell Death and Differentiation, Vol. 15, 51-57, 2008) shows clearly in Figure 1 both direct and indirect actions of dendritic cells on tumor cell targets. Yet, those direct mechanisms such as NO require close proximity to tumor cells for functionality. Thus, intratumoral administration of poly6 would be required to predictably affect tumor cells with local dendritic cells. Wesa notes that they have not identified NO to directly promote tumor cell death but rather to reduce expression of the anti-apoptotic protein like surviving in treated tumor cells (Pg. 55, Column 2, Paragraph, second). This again makes clear that administration of poly6 intratumorally is required.
Furthermore, even when human killer dendritic cells (KDC) are present they do not always kill target tumor cells as noted by Wesa in their inability to kill K562 cells but ability to kill Jurkat cells (Pg. 52, Column 1, Paragraph, first). Thus, some such human cells will kill T cell leukemia but not a chronic myelogenous leukemia. Therefore, use of human KDC is not predictable to treat just any cancer. A PHOSITA would therefore need to be shown data verifying functionality of the claimed methods. It is noted that Applicant used DC2.4 cells in their experiments of example 3. These are murine dendritic cells which Wesa notes are not identical in phenotype to human KDC stating clearly that a true counterpart to the murine NKDC population has yet to be identified in humans (Pg. 52-53, Paragraph, spanning).
Taken together, to treat tumors in humans with SEQ ID NO. 1, evidence must be shown that human dendritic cells are stimulated thereby to become activated KDC and such should be tested against tumor cell types to determine which are sensitive to such human DC. However, Applicant only provides murine DC experiments in vitro or mouse models for in vivo experiments. In view of the differences between human DC and murine DC, as well as the unpredictability of human DC functionality against tumors as evidenced by Wesa, more data is needed from at least in vitro experiments with human DC to show functionality of the claimed methods in humans.
With respect to cancer prevention, no material has been found to date that has been shown to or would be expected to prevent cancer, and there is no working example, prior art, or any evidence that would provide the skilled artisan with any predictable guidance to use the claimed invention. It would be reasonable to conclude the claimed invention is not enabled.
Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations that have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, or family histories. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Further, a preventive administration also must assume that the therapeutic will be safe and tolerable for anyone susceptible to the disease.
The vaccine art teaches that compositions comprising some tumor associated antigens are effective in treatment of cancer through generation of immunogenic response to the tumor antigen (see for example, Komenaka et Al., Clinics in Dermatology, 2004, Vol. 22, Pg. 251-265, specifically page 257). However, nowhere in the art does it show that tumor antigens are effective at preventing cancer. Evans et Al. (Q. J. Med 1999: 92: 299-307) teach that vaccines against cancer are not fully established, and it is stated that adjuvant therapy to prevent or delay disease still needs experimentation. Evans et Al. further state that such cancer vaccines are at best used as a therapeutic and not as a prophylactic and that “the notion that cancer vaccines will replace standard therapeutic strategies in malignant disease still belongs to the realm of fiction” (see page 303 last paragraph).
In some cases, it is known that certain cancers arise from a single cause. This cause can be viral as in the case of cervical cancer, caused predominantly by persistent cervical infection with human papillomavirus (HPV) (Schiffman et Al., The New England Journal of Medicine, Vo. 353, No. 20, Pg. 2101-2104, 2005). Schiffman et Al. teach that primary prevention through vaccination against HPV might be possible in young women (Pg. 2101, Column 3, Paragraph, first paragraph). However, they also teach that vaccine evaluations are ongoing (Pg. 2103, Column 3, Paragraph, first full). In addition, the most promising vaccines designed against HPV types 16 and 18 would only prevent 70 percent of cervical cancer cases at best (Pg. 2103, Column 2, Paragraph, first full). Therefore, there is still no vaccine that can definitively prevent a cancer. Current evidence points only to the potential of future prophylactic agents.
The art of small molecule chemotherapeutics teaches that some molecules successful at treating cancers can also reduce risk. Cuzick et Al. (The Lancet, Vol. 361, Pg. 296-300, 2003) teach that tamoxifen can reduce the risk of ER-positive breast cancer but cannot be recommended as a preventive agent (Pg. 299, Column 2, Paragraph, first). The reason it cannot be recommended centers around the need for continued research into specific subgroups of high-risk but healthy women for whom the risk-benefit ratio is sufficiently positive to recommend prophylactic tamoxifen treatment (Pg. 299, Column 2, Paragraph, first).
With respect to peptide-based cancer prevention agents, the art currently does not recognize a definitive example though promising candidates are present. Hernandez-Ledesma (Peptides, Vol. 30, Pg. 426-430, 2009) teaches that lunasin, a peptide discovered in soy has demonstrated cancer-preventative capacity in vitro and mouse models (Abstract). The authors define it as a perfect candidate to exert an in vivo cancer-preventive activity but more research is required to establish it in this role (Pg. 429, Column 2, Paragraph, first partial).
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
New Rejections Based on Amendments
Claim Objections
Claim 38 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 35. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 27 is objected to because of the following informalities: Claim 27 recites the limitation “…checkpoint inhibitor is an anti-PD-L1”. It is not known what an “anti- PD-L1” is. The specification does not clarify what it is and Fig. 27 A, B, C and D does not provide further clarification. An appropriate recitation would be an anti-PD-L1 antibody based on how antibodies are generally named.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claim 37 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 37 recites: “A method of treating nitric oxide (NO)-dependent cancer,….”. However, the specification does not clearly define what a nitric oxide (NO)-dependent cancer is. It could be that the cancer must have arisen in response to NO signaling. It could be that the cancer depends on NO for vascularization. It could be the cancer depends on NO to control immune cell entry into the tumor microenvironment and thus evade the same. The presence of multiple very different interpretations renders the claims indefinite.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
2. Claims 21-40 are rejected under 35 U.S.C. 103 as being unpatentable over Lasters (previously cited) in view of Martinez (cited previously), Veglia (cited previously) and Dou (cited previously) and Labarriere (WO2013/175258 publication date 11/28/2013).
Lasters teaches 9 aminoacidic peptides (SEQ ID NOs; 732-735, page 90) that comprise SEQ ID NO: 1 (see alignment for SEQ ID NO: 732 LQHGRLVFQ in the FAOM dated 09/12/2025 ) derived from HBV that can generate a strong CTL (CD8 T cells) response (page 9, third paragraph). In addition, these peptides are 13 or less in length (page 18, second paragraph) and the peptides can be modified by extending, decreasing or substituting amino acids in the peptide sequence by, for example, the addition or deletion of amino acids on either the amino terminal or carboxy terminal end, or both (page 35, last paragraph). That is, the peptide can be also just 6 amino acids long (instant claims 35, 36 and 38 (duplicate of 35)). This antigen can be presented by a dendritic cell (page 54, second paragraph) in its role as an APC (antigen-presenting cell) and thus is activated. Because the peptides taught by Lasters comprise the instant SEQ ID NO: 1, including the 6 amino acids long peptide consisting of SEQ ID NO:1 (instant claims 35, 36 and 38 (duplicate of 35), they would inherently have the same activity and functionality as the claimed polypeptide comprising instant SEQ ID NO: 1 and thus could be used for the same methods of treating cancer (including NO-Dependent cancer) enhancing anticancer immunity, and the same function of activating dendritic cells, so they can present the peptide as an antigen, and T cells, as required in claims 28-29 and 37. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same...[footnote omitted].” In particular, Laster’s peptides activate dendritic and CTL (CD8) cells (as required by claim 22 and 29) and thus generate a strong CTL response (as required by claim 28). This strong CTL response is needed for both antiviral (HBV for example) and cancer treatment (see discussion on Martinez and Labarriere below).In addition, Lasters teaches that their invention is directed to pharmaceutical and vaccine compositions that contain as an active ingredient an immunogenically effective amount of a cytotoxic T-lymphocyte stimulating peptide, as described herein. The peptide(s) may be introduced into a host, including humans (page 47 last paragraph) and thus, are useful for administration to mammals, particularly humans (page 54, 5th paragraph) as required by instant claims 38 (duplicate of 35), 39 and 40. Applicants have confirmed in their arguments (see page 4, first paragraph above that the peptide of SEQ ID NO. 1, is not specific to colorectal cancer but exhibits non-specific immune-inducing ability across various cancer types, that is, acts as an adjuvant with a non-specific immune response.
Lasters does not teach the direct use of the peptides as a method for cancer, as required in claims 21- 24 and 31. Laster does not teach the type of dendritic cells, such as the dendritic cells expressing iNOS (inducible nitric oxide synthase enzyme that generates nitric oxide (NO)), or TNF-alpha, also known as Tip-DC, as required by claims 23 and 30. Lasters does not teach the further administration of a checkpoint inhibitor, such as and anti-PD-L1, as required by claims 25-27 and 32-34.
Martinez teaches how cytotoxic lymphocytes including CTL cells kill cancer cells (entire article) and that CTLs are ultimately responsible for killing any cancer cell and eradicating the tumor (abstract) as required by claims 21-23 and, since CTLs can kill any cancer cell, claims 24 and 31. Martinez teach that dendritic cell are needed to activate CTLs (figure 1) but does not teach subtypes of dendritic cells as required by claims 23 and 30.
Veglia teaches the role of dendritic cells in cancer (entire article). The presence of inflammatory dendritic cells correlated with CD8 T (CTL) cell activation and treatment success in several tumor models, and that a subset of inflammatory dendritic cells producing TNF-alpha and NO (Tip-DCs) (NO produced by iNOS) are expanded and activated after adoptive T-cell transfer (ACT) (that is, T cells are needed) and are necessary for tumor growth control (page 5, fourth paragraph). Tip-DC cells are required by claims 23 and 30.
Labarriere teaches a melanoma antigen peptide for use in the prevention or the treatment of melanoma in patient (Page 1, field of the invention, page 3, summary of the invention) (melanoma is recited in instant claims 24 and 31). In antitumor immune responses, CD8 cytotoxic T lymphocytes (CTL) have been identified as the most powerful effector cells (page 1, line 14-15). This teaching is consistent with the teachings of Lasters, Martinez and Veglia. The term “peptide” encompasses amino acid sequences having less than 50 amino acids, less than 40 amino acids, less than 30 amino acids, less than 25 amino acids, less than 20 amino acids, less than 15 amino acids or less than 10 amino acids (page 3 Definitions Line 21-26). Therefore, Labarriere reads on short peptides less than 10 amino acid in length used previously as vaccines for the treatment of melanoma.
Lasters, Martinez, Veglia and Labarriere do not teach the further administration of a checkpoint inhibitor, such as and anti-PD-L1, as required by claims 25-27 and 32-34.
Dou teaches HBV derived peptides that can boost CD4 (helper) and CD8 T (CTL) cell responses (entire article). In particular, Dou discloses that in six out of seven patients, a blockade of PD-L1 further increased the peptide effects (Abstract: results) (instant claims 25-27 and 32-34).
It would have been obvious to one of ordinary skill in the art to combine the teachings of Lasters with Martinez, Veglia and Labarriere to develop a method, using a peptide comprising or consisting of SEQ ID NO: 1, to enhance immunity by generating a strong CTL response involving dendritic cells (as taught by Lasters). These dendritic cells needed for CTL activation can include Tip-DC cells (as taught by Veglia). It would be also obvious that this enhanced immunity involving dendritic cells (including Tip-DC) and CTL cells could be further developed as a method of treating cancer because CTL kill cancer cells (as taught by Martinez) and Tip-DC are necessary for tumor growth control. In addition, short peptides are known to be useful for melanoma treatment (Labarriere) so it would be obvious to try the use of the instant peptide for treatment of cancer such a melanoma. One of ordinary skill would have been motivated to do so because any peptide comprising and/or consisting of SEQ ID NO: 1, will act as an adjuvant inducing a non-specific immune response, activate dendritic cells to generate a strong CTL response, which is needed to treat any cancer. There would be a reasonable expectation of success because Veglia teaches that inflammatory dendritic cells including Tip-Dc together with CTLs have been successful in several tumor models and in tumor growth control and Labarriere teaches short peptides enabled to treat melanoma.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Lasters, Martinez, Veglia and Labarriere, as discussed above, with Dou and administer a checkpoint inhibitor (an anti-PD-L1) together with the polypeptide comprising SEQ ID NO: 1 to a subject to either enhance anticancer immunity or treat cancer. One of ordinary skill would have been motivated to do so because both: the polypeptide comprising SEQ ID NO 1 and an anti-PD-L1, act on the immune system. There would be a reasonable expectation of success because Dou teaches that the combination of peptides with a blockage of PD-L1 can enhance the effect of a peptide and boost the immune response..
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Regarding the interpretive “wherein” clauses (“…wherein the polypeptide activates dendritic cells and increases the expression of at least one selected from the group consisting of TNF-a and iNOS in dendritic cells”), (claims 21, 28 and 37); (“…wherein the polypeptide further activates T cells”), (claims 22 and 29), (…wherein the polypeptide increases the expression of TNF-alpha and iNOS in dendritic cells”), (claims 23 and 30), these wherein clauses do not recite any additional active method steps but simply states a characterization or conclusion of the results of those steps. The court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. Here, the wherein clauses of claims 21-23, 28-30, and 37 only recite the intended result of the active steps recited and so said clauses are not given weight but would necessarily occur upon performance of the steps.
Even if one were to consider that the wherein clauses could be limiting based on the effective treatment doses, Lasters teaches that in therapeutic applications, compositions are administered to a patient in an amount sufficient to elicit an effective cytotoxic T lymphocyte response and to cure or at least partially arrest symptoms and/or complications (a "therapeutically or prophylactically effective dose" which is also an "immune response provoking amount.") (page 41, 2nd paragraph). Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. The present inventive method typically will involve the administration of about 0.1 μg to about 50 mg of one or more of the compounds described above per kg body weight of the individual (page 41, 3rd paragraph). It would further be obvious to a person of ordinary skill in the art that the compound dosages in a composition are clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient needed to achieve the desired results. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." (Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 2. Thus, before filing one of ordinary skill in this art would have identified a functional, optimal dose of SEQ ID NO. 1 for cancer treatment even in the case of the peptide being used as an adjuvant. At such a dose, all intended results of the instant claims will necessarily occur.
Applicant' s arguments have been fully considered and are not persuasive.
Applicant' s Arguments:
- Lasters discloses that the claimed peptide "can be presented by a dendritic cell and thus is activated." However, Lasters does not disclose anywhere that the peptides that allegedly correspond to the claimed polypeptide (e.g., SEQ ID NOS: 732-735) were in fact successful in activating dendritic cells. Lasters merely states that its invention includes an "antigen presenting cell that comprises one or more epitopes" without clearly establishing that the "one or more epitopes" includes peptides of SEQ ID NOS: 732-735. Moreover, Lasters does not state anywhere that a dendritic cell that presents an epitope is necessarily activated by the epitope. Furthermore, Lasters merely includes SEQ ID NOS: 732-735 in a list of more than 400 peptides to be tested in vitro for CTL activity rather than activation of dendritic cells and provides no evidence that these four peptides in fact demonstrated any response.
The office action relies on the alleged teaching that the claimed peptide provides "a strong CTL response involving dendritic cells (as taught by Lasters)." Because Lasters fails to teach that the peptides having sequences set forth in SEQ ID NOS: 732-735 activate dendritic cells or induce any CTL response for the reasons explained above, a POSITA would not have considered Lasters' peptides having sequences set forth in SEQ ID NOS: 732-735 for use in treating cancer. Moreover, present specification shows that a statistically significant Tip-DC population was formed in the group stimulated by the poly6 (see, e.g., Specification at [0190] and Fig. 22), and results confirm that poly6 induces a direct anticancer effect by inducing differentiation of dendritic cells into Tip-DCs in vivo In addition, an anticancer effect was confirmed in T-cell-deficient balb/c nu/nu mice, and results supporting the direct anticancer induction ability of Tip- DCs were confirmed in that they induce an anticancer effect mediated by innate immune cells.
- Neither Lasters nor Martinez discloses anything regarding Tip-DCs at all, but merely disclose that they act as a center of adaptive immunity, such as CD8 T cells. Furthermore, in Veglia, the sequence of poly6 is not disclosed as an active ingredient, and while it discloses that Tip- DC exhibits a tumor growth inhibitory effect through CD8 T cell activation, it does not describe the specific confirmation of a direct anticancer effect caused by the activation of Tip-DC by Poly6. Therefore, based on these results, administering a polypeptide consisting of the amino acid sequence of SEQ ID NO. 1 to a subject results in activation of dendritic cells and increase in the expression of at least one selected from the group consisting of TNF-a and iNOS in the dendritic cells, thereby exhibiting Tip-DC activity and directly showing an anticancer effect regardless of the type of cancer without a CTL response by T cells. Such therapeutic effect of increasing the activity of such direct Tip-DCs to exhibit an anticancer effect even without a CTL response is not obvious from the combination of Lasters, Matinez, and Veglia.
Examiner' s Response to Arguments Applicant's arguments have been carefully considered but are not found persuasive.
- As discussed in detail in the previous office actions, Lasters teaches 9 aminoacidic peptides (SEQ ID NOs; 732-735, page 90) that comprise SEQ ID NO: 1 derived from HBV that can generate a strong CTL (CD8 T cells) response (page 9, third paragraph) and can be presented by a dendritic cell (page 54, second paragraph) in its role as an APC (antigen-presenting cell) and thus is the dendritic cell is activated.
Regarding the latent properties discussed in the wherein clauses, “[m]ere recognition of those latent properties does not render the otherwise obvious [method] unobvious and thereby patentable.” In re Prindle, 297 F.2d 251, 254 (CCPA 1962). Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979).
In response to applicant’s argument that, the fact that applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In addition, applicant has not provided working examples in commensurate with the scope of the instant claims (treatment or prevention of any cancer)
Prior art is presumed to be operable/enabling (MPEP 2121). The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970).
Applicant is reminded that when the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to provide facts rebutting the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). Objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the applicant. Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art. 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). Thus, Applicants’ arguments that Laster is nonenabling (e.g., inoperable) are not found persuasive in the absence of objective evidence. There is no reason to believe that a POSITA would not have considered Lasters' peptides (SEQ ID NOS: 732-735) for use in treating cancer because Laster’s invention claims these peptides activate dendritic cells and/or induce any CTL response.
- As discussed in detail in the previous office actions, The combined teachings of Lasters with Martinez, Veglia (and Labarriere) to develop a method, using a peptide comprising SEQ ID NO: 1, to enhance anticancer immunity by generating a strong CTL response involving dendritic cells including Tip-DC cells. Applicant argues that neither Lasters nor Martinez discloses Tip-DC only that they act as a center of adaptive immunity, such as CD8 T cells. Furthermore, in Veglia, the sequence of poly6 is not disclosed as an active ingredient. However, 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). Applicant has not sufficiently described why there is no prima facie case for obviousness.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (for example: poly6 induces a direct anticancer effect by inducing differentiation of dendritic cells into Tip-DCs in vivo In addition, an anticancer effect was confirmed in T-cell-deficient balb/c nu/nu mice, and results supporting the direct anticancer induction ability of Tip- DCs were confirmed in that they induce an anticancer effect mediated by innate immune cells. Tip- DC exhibits a tumor growth inhibitory effect through CD8 T cell activation, it does not describe the specific confirmation of a direct anticancer effect caused by the activation of Tip-DC by Poly6, etc.). are not recited in the rejected claim(s). Tip- DCs are not recited in the claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
Conclusion
Claims stand rejected.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/Michael Allen/Supervisory Patent Examiner, Art Unit 1671
