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 .
Status of Claims
The amended claims filed 12/12/2025 are acknowledged and entered.
Claims 21, 24, 28 and 31 have been amended
Claims 1-20 are cancelled
Claims 35-37 have been added.
Claims 21-37 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Claim Rejections - 35 USC § 102 - Withdrawn
2. The rejections of claims 28-29 under 35 U.S.C. 102(a)(b) as anticipated by Lasters (cited previously), are withdrawn in view of Applicant’s amendments to claim 28.
Claim Rejections - 35 USC § 112 - Maintained
1. Claims 21-34 and newly added claims 35-37 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 for a method of treating mice 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 preventing any cancer (including nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer) in any subject (as required by claims 21-27 and 35) or for a method of enhancing anticancer immunity in any subject (if the subject is not a subject suffering from cancer then the enhancement of anticancer immunity can be interpreted as a way to prevent any cancer (including nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer)) as required in claims 28-34 and 36. The specification does not reasonably provide enablement for a method of treating all forms of nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer in any subject (instant claim 37). 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.
The instant specification fails to provide information that would allow the skilled artisan to fully practice the instant invention without undue experimentation. Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention: Claims 21-27 and 35 of the instant application are drawn to a method of treating or preventing nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer in a subject in need thereof, comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 1 in any subject. This method may further comprise administering a check point inhibitor such as an anti-PD-L1. Claims 28-34 and 36 of the instant application are drawn to a method of enhancing anticancer immunity in a subject in need thereof, comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 1. This method may further comprise administering a checkpoint inhibitor such as an anti-PD-L1. Therefore, the invention encompasses preventing nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer in a subject in need thereof (any and all subjects are in need of not developing cancer). Claim 37 is drawn to a method of treating NO-dependent cancer, comprising administering a polypeptide to a subject in need. Therefore, the invention also encompasses treating a very wide range of types of nitric oxide (NO)-dependent cancers, colon cancers, melanoma, pancreatic cancers, and breast cancers in a subject in need thereof. Regarding claims 28 and 37, the specification shows that polypeptide(p6)- induced DC2.4 cells (immortalized mouse dendritic cell line) induced direct cytotoxicity in MC38 (colon) and B16F10 (melanoma) cancer cells (page 25-26, sections 3-4) and showed enhanced anticancer immunity when the polypeptide is used as an adjuvant when treated in combination with an anti-PD-L1 (page 30, section 6). Therefore p6 is enabled to use in colon cancer and melanoma in animal models.
Breadth of the claims: The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. The rejected claims are extremely broad. Applicant claims that the polypeptide, (with or without a checkpoint inhibitor), can be used to prevent or treating nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer in any subject. Thus, the cited claims are deemed very broad since these claims read on essentially preventing or treating a broad group of cancers in any subject comprising the administration of the claimed polypeptide.
State of the Prior Art: While the state of the art with regard to the treatment of cancer is relatively high, the state of the art with regard to the prevention of cancer is underdeveloped. This is because there would be no way to determine that cancer would have predictably occurred without treatment.
Regarding prevention of cancer, the American Cancer Society maintains that “There's no sure way to prevent cancer. (This statement also applies to nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer) but you can help reduce your risk by making healthy choices like eating right, staying active, and not smoking” (American Cancer Society. Cancer Risk and Prevention. https://www.cancer.org/cancer/risk-prevention.html). Regarding the treatment of cancer, therapeutics are designed for very specific cancer types and very specific patient population. It is very uncommon that one single therapeutic could successfully treat such a broad and unrelated cancers as listed in the claims.
Predictability/Unpredictability in the Art: It is noted that the vaccine art is unpredictable, requiring each embodiment to be individually assessed for physiological activity in preventing diseases. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the recitation encompasses the prevention of nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer and treating any subject in need thereof. Thus, the skilled artisan would view that the prevention of these types of cancers encompassed by the claims, (by administering to the subject a polypeptide comprising the amino acid sequence of SEQ ID NO: 1, (and this administration may further comprise administering a checkpoint inhibitor), is highly unpredictable. In addition, treating all types of nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer in any subject successfully with a peptide (with or without a check point inhibitor) is highly unpredictable as cancer treatments usually are specific for a few types of very related cancer in a very specific patient population.
Guidance of the Specification/Working Examples: Applicant has only provided working examples suggesting that the vaccines and antibodies may treat some specific cancer cells in mice. Thus, the specification fails to provide sufficient evidence in support of prevention or treatment of all types of nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer in any subject as recited in the instant claims.
Additionally, the examples provided do not demonstrate the prevention or treatment of any type of nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer. Additionally, the disclosure does not discuss, or demonstrate through working examples, a method that could be used to determine that recurrence of diseases/disorders was prevented using the claimed agents as there is no disclosed method to determine that recurrence of nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer would have predictably occurred without treatment.
The Quantitation of Experimentation Required: In order to practice Applicant’s invention, it would be necessary for one to design and conduct an exhaustive amount of complex experiments to demonstrate that the claimed polypeptide could be administered to a subject. To prevent this group of cancers, the population of subjects could include any subject, and thus the quantitation of experimentation is unreasonably large. Therefore, in order to practice the claimed invention, the amount of experimentation required would be considered undue and burdensome. In addition, determination of which cancer types and which group of patients would be successfully treated using this polypeptide would also require an exhaustive amount of complex experiments and undue experimentation,
In conclusion, Genentech, 108 F.3d at 1366, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”. The prevention and treatment of nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer is not enabled by the instant specification.
Claim Rejections - 35 USC § 103 - Maintained
3. Claims 21-24, 28-31 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Lasters in view of Martinez (cited previously), and Veglia (cited previously)
Lasters teaches 9 aminoacidic peptides (SEQ ID NOs; 732-735, page 90) that comprise SEQ ID NO: 1 (see alignment below for SEQ ID NO: 732 LQHGRLVFQ) 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 and 36). 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. That is, Laster’s peptides (instant claim 21) activate dendritic and CTL (CD8) cells (as required by instant claims 22 and 29) and thus generate a strong CTL response (as required by instant claim 28).This strong CTL response is needed for both antiviral (HBV for example) and cancer treatment (see discussion on Martinez below)
Because the peptides taught by Lasters comprise the instant SEQ ID NO: 1, and included the 6 amino acid peptide, they would inherently have the same activity and functionality as the polypeptide comprising instant SEQ ID NO: 1 and thus could be used for the same methods of 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. 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].”
SEQUENCE ALIGMENT FOR SEQ ID NO: 1 VERSUS SEQ ID NO: 732
Title: US-18-021-262-1
Perfect score: 30
Sequence: 1 GRLVFQ 6
AC ADQ12933;
DT 07-OCT-2004 (first entry)
DE Hepatitis B virus MHC class I restricted T-cell stimulating peptide 732.
CC PN WO2004058807-A2.
CC PD 15-JUL-2004.
CC PI Lasters I, Desmet J, Stegmann T, Castelein B;
CC PS Example 7; SEQ ID NO 732; 108pp; English.
SQ Sequence 9 AA;
Query Match 100.0%; Score 30; Length 9;
Best Local Similarity 100.0%;
Matches 6; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GRLVFQ 6
||||||
Db 4 GRLVFQ 9
Lasters does not teach the use of the peptides as a method for treating cancer, as required in claims 21- 24, 31 and 35. 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.
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 21-24, 31 and 37 (any cancer includes nitric oxide (NO)-dependent cancer, colon cancer, melanoma, pancreatic cancer, and breast cancer). 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.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Lasters with Martinez and Veglia 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 (as taught by Lasters). These dendritic cells needed for CTL activation include Tip-DC cells (as taught by Veglia). It would be also obvious that this enhanced anti-cancer immunity involving dendritic cells (including Tip-DC) and CTL cells could be further developed as a method of treating cancer because CTL cells kill any cancer cells (as taught by Martinez) and Tip-DC are necessary for tumor growth control. One of ordinary skill would have been motivated to do so because any peptide comprising SEQ ID NO: 1, can 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.
It would further be obvious with that the peptide length is 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 length of the peptide 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.
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.
Claims 1-37 are rejected under 35 U.S.C. 103 as being unpatentable over Lasters in view of Martinez, Veglia and Dou (cited previously)
Lasters, Martinez and Veglia teachings have been discussed above and applied herein. Lasters, Martinez and Veglia 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, Martinez and Veglia 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.
Relevant arguments that apply to new claims
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejection is maintained.
Applicant’s arguments are as follow:
- (a) Applicant has amended claims 21 and 28, and 24 and 31 to better capture commercial embodiments limited to nitric oxide-dependent cancer and further to colon cancer, melanoma, pancreatic cancer, and breast cancer. The specification provides sufficient enablement for the claimed invention.
- (b) Lasters discloses that its "CTL-inducing polypeptides of the invention are 13 residues or less in length and usually consists of between about 8 and about 11 residues, preferably 9 or 10 residues." To the contrary the peptide sequence claimed in pending claims 28 consists of 6 amino acids. Accordingly, Lasters fails to disclose each and every feature of claim 28, on which claim 29 depends, and therefore fails to anticipate these claims. For the same reason, Lasters fails to anticipate newly introduced claim 36.
Moreover, Lasters pertains to use of a peptide "for the treatment and prevention of HBV”. See Lasters at Title, Abstract, Aims of the Invention ("It is an aim of the invention to provide immunogenic peptides which may be used for the preparation of therapeutic and prophylactic vaccines for the treatment and prevention of HBV infections."). Lasters does not disclose that the peptide can be used for enhancing the immunity against any types of cancer, let alone nitric oxide-dependent cancers. Thus, even when it is assumed, arguendo, that the claimed peptide is disclosed in Lasters, the unexpected cancer-treating property of the claimed peptide is patentable over the teachings of Lasters confined to treatment and prevention of HBV infections. See MPEP § 2112.02.11 (stating that patent claims describing unexpected effects of a known compound are patentable (citing In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978)).
- (c) Claims 21-24 and 28-31 are rejected as allegedly being unpatentable over Lasters in view of Martinez and Veglia. Moreover, claims 1-34 are rejected as allegedly being unpatentable over Lasters in view of Martinez, Veglia and Dou.
Lasters fails to disclose each and every feature of claims 21 and 28, on which all other rejected claims depend, including the claimed peptide and the methods of treating, preventing, or enhancing immunity against nitric oxide-dependent cancers. Martinez, Veglia and Dou fail to remedy this deficiency in Lasters. For the same reasons the cited references, whether individual or in the combination proposed in the office action, fails to disclose each and every feature of newly introduced claims 35 and 6.
Applicant’s arguments have been considered. In response to Applicant’s arguments:
- Regarding item (a), as discussed in the Claim Rejections - 35 USC § 112 section above, The specification does not provide sufficient enablement for the claimed invention. In addition, it is unclear what it is meant by “commercial embodiments limited to nitric oxide-dependent cancer and further to colon cancer, melanoma, pancreatic cancer, and breast cancer” argument. If applicant refers to products already approved by the FDA and available to the public, capable of preventing cancer or treating such a wide range of cancer types in any subject to address the Wands factors: “state of the prior art” and/or the “predictability/unpredictability of the art”, applicant has not provided examples of any such products.
- Regarding item (b), Claims 21, 28 and 37 recite the term “comprising of”. The transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., > Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) (“like the term comprising,’ the terms containing’ and mixture’ are open-ended.”).< Invitrogen Corp. v. Biocrest Mfg., L.P., 327 F.3d 1364, 1368, 66 USPQ2d 1631, 1634 (Fed. Cir. 2003). MPEP 2111.02. Lasters peptide does comprise the claimed SEQ ID NO: 1 (see sequence alignment above).
Newly added claims 35 and 36 are rejected under 35 U.S.C. 103 as Lasters teaches that the peptides can be less than 13 amino acids (which does not exclude a peptide being 6 amino acids long, even if the peptide usually consists of between about 8 and about 11 residues, preferably 9 or 10 residues ) and/or can be modified by deleting amino acids (see rejection above).
Regarding Applicant’s argument that Lasters teaches the use of a peptide "for the treatment and prevention of HBV. Lasters does not directly disclose that the peptide can be used for enhancing the immunity against any types of cancer is found persuasive and the rejections of claims 28-29 under 35 U.S.C. 102(a)(b) is withdrawn.
- Regarding item (c), Applicant’s argument that Lasters fails to disclose each and every feature of claims 21 and 28 seems to be directed to the rejections under 35 U.S.C. 102, which has been withdrawn. Regarding the rejections under 35 U.S.C. 103, 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). Whereas Lasters teaches the peptide, Martinez, Veglia and Dou teach the remaining limitations. Applicant has not sufficiently described why there is no prima facie case for obviousness. See discussion above for more details regarding the teachings of Lasters, Martinez, Veglia and Dou relevant to the rejection under 35 U.S.C. 103 and the motivation to combine these references.
Applicant argues as set forth above. Thus, for the reasons set forth above and the reasons of record, the rejections under 35 U.S.C. 103 are maintained.
Conclusion
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.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/Michael Allen/ Supervisory Patent Examiner, Art Unit 1671