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 .
Claims Status
The remarks filed 07/09/2026 are acknowledged.
Claims 1-20 are pending.
Applicant’s election without traverse of Group I, claims 1-19, in the reply filed on 07/09/2026 is acknowledged. Applicant’s election without traverse of the following species in the reply filed on 07/09/2026 is acknowledged: a chimeric protein for what is administered in the method of treating cancer, a genetically modified NK cell for the specific NK cell, contemporaneous administration, and low dose chemotherapy for what the method further comprises.
Claims 1-13 and 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/09/2026.
Therefore, claims 14-17 are under examination.
Priority
The instant application is a CON of 17/274,127 (now U.S. Patent No. 12,098,177) which claims priority to provisional application 62/728,510. Priority is given with the earliest effective filing date of 09/07/2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 12/18/2024, 03/19/2025, 06/25/2025, 05/06/2026, and 06/18/2026 are in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement is being considered by the examiner.
The document lined through on the 03/19/2025 IDS (NPL Cite No. 7) was not considered because it was not attached.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specification
The disclosure is objected to because it contains embedded hyperlinks and/or other forms of browser-executable code (see paragraph [0048] of the specification). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 14 is objected to because of the following informalities: Claim 14 recites an acronym (i.e. IL-12). The first time an acronym is used, it must be accompanied by the definition of the abbreviation. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(9b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 16 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 16 recites the limitation “wherein the cancer cell targeting portion comprises an antibody heavy chain having the sequence of amino acids 539-991 of SEQ ID NO: 2 and an antibody light chain having the sequence of amino acids 24-236 of SEQ ID NO: 3.” There is no sequence listing in the application and thus, it is unclear what sequences SEQ ID NO: 2 and SEQ ID NO: 3 are referring to. Therefore, the scope of this claim is indefinite.
Note: The instant application is a CON of parent application 17/274,127 (now U.S. Patent No. 12,098,177). For compact prosecution and examination purposes, the Examiner is relying on the sequence listing of the parent application and making the assumption that SEQ ID NOs: 2 and 3 of the parent application are the same as SEQ ID NOs: 2 and 3 of the instant application, respectively.
Claim 17 recites the limitation “low dose chemotherapy”. Applicant does not provide an explicit definition for “low dose chemotherapy”. However, the metes and bounds for “low dose” are dependent on the interpretation of others for determining what is a “low dose”. Given a single dose, one person of ordinary skill in the art could determine that the value is a low dose. Yet, another person of ordinary skill in the art
could determine that it is not a low dose, leading to two different interpretations on if the
claim infringes with “low dose.” Therefore, the scope of this claim is indefinite.
For examination purposes, the Examiner is interpreting “low dose chemotherapy” as being any dose that is lower than the standard, conventional dosing for the specific chemotherapy drug.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 14-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 14 is drawn to a method of treatment for cancer in a patient in need thereof, the method comprising administration of an effective amount of a chimeric protein comprising an IL-12 portion and a cancer cell targeting portion; wherein the chimeric protein comprises in a single polypeptide sequence a single chain IL-12 comprising an IL-12a subunit and a IL-12B subunit coupled to each other via a peptide linker. Thus, the claims broadly encompass treating the genus of all cancers.
The specification teaches that the binding specificity of the chimeric proteins HuIL-12/Hu51-4 and MuIL-12/Hu51-4 were evaluated on Raji cancer cells (human Burkitt’s lymphoma cells) and that the chimeric proteins did bind to the cells [see paragraph 77 of the specification]. However, this does not indicate that the chimeric proteins actually treated the lymphoma.
The claims encompass far more than a specific chimeric protein that binds to lymphoma cells. The claims broadly encompass treating all cancers using the aforementioned method. Cooper, 2000 (instant PTO-892) teaches that cancer can result from abnormal proliferation of any of the different kinds of cells in the body [see Types of Cancer section]. Cooper further teaches that there are more than a hundred distinct types of cancer, which can vary substantially in their behavior and response to treatment [see Types of Cancer section].
The specification teaches that the chimeric protein binds to human Burkitt’s lymphoma cells; however, this is not deemed to be predicative of the response of all cancers to the claimed cancer regimen. The specification is not deemed sufficient to reasonably convey to one skilled in the art that the inventors, at the time the invention was made, had possession of a method of treating all cancers within the broad genus because the genus encompasses conditions which differ from those disclosed in etiologies, molecular mechanisms, diagnostic approaches, treatment modalities, and therapeutic endpoints.
In regards to the present invention of a method of treating cancer, comprising administering the generic chimeric protein to a patient, Tugues et al., 2014 (instant PTO-892) teaches that antitumor (cancer) treatments with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects [see Abstract]. Similarly, Lasek et al., 2014 (instant PTO-892) teaches that IL-12 is considered to be incapable of directly inhibiting cancer growth and that toxicities of IL-12 administration seem to prevail over its antitumor effectiveness [page 420, right column, first paragraph].
Furthermore, the recited genus encompasses conditions yet to be discovered and/or characterized; therefore, the skilled artisan cannot envision preventing all the contemplated diseases encompassed by the instant claims. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
It is known in the art that cancer cells arising from different tissues differ in etiology and response to treatment. Heppner and Miller, 1983 (instant PTO-892) discuss the heterogeneity of tumors from different tissues and from the same tissue. Heppner and Miller teach that the heterogeneity of tumors contributes to the sensitivity the tumor will have to drugs [Summary, third paragraph]. Heppner and Miller further teach that as a tumor progresses to a metastatic phenotype, the way the tumor responds to treatment can differ, and thus, make it difficult to predict how the tumor will respond to the treatment [Page 15, right column, first paragraph].
The prior art demonstrates that IL-12 failed to show sustained antitumor responses, IL-12 is incapable of directly inhibiting cancer growth, and that IL-12 administration is associated to toxic side effects that prevail over its antitumor effectiveness. Accordingly, one of skill in the art would conclude that the claimed invention encompasses a broad genus of cancers that may not respond to treatment with the chimeric protein comprising an IL-12 portion and a cancer cell targeting portion. As such, one of skill in the art would not deem the prior art in cancer treatment to be predicative of the efficacy of the claim treatment regimen in all cancers. Based on the teaching of the instant specification and the prior art, one of skill in the art would not conclude that Applicant was in possession of the claimed method of treating any cancer.
Enablement
Claims 14-15 and 17 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 colon cancer comprising administering an antibody fusion protein comprising a murine single chain IL-12 (IL-12 beta subunit linked to the IL-12 alpha subunit) fused to an anti-Her2/neu antibody, does not reasonably provide enablement for a method of treating any cancer comprising administering a chimeric protein comprising an IL-12 portion and any cancer cell targeting portion, wherein the chimeric protein comprises in a single polypeptide sequence a single chain IL-12 comprising an IL-12α subunit and a IL-12β subunit coupled to each other via a peptide linker. 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.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and
Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v.
Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or 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. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
The claims are drawn to a method of treating any cancer in a patient in need thereof comprising administering a chimeric protein comprising an IL-12 portion and any cancer cell targeting portion, wherein the chimeric protein comprises in a single polypeptide sequence a single chain IL-12 comprising an IL-12α subunit and a IL-12β subunit coupled to each other via a peptide linker.
The claims are broad and inclusive of all types of cancer or neoplasia in humans generally. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. The claims are extremely broad due to the vast number of possible cancer types and tumor cell growth mechanisms represented by the phrase “treatment for cancer.” Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body.
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regard to treating cancer broadly is underdeveloped. In particular, there is no known anticancer treatment that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability and has long been underdeveloped with regard to the treatment of cancers broadly. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all cancers with the claimed method makes practicing the claimed invention unpredictable.
With regard to the instant invention, Applicant is enabled for a method of treating colon cancer comprising administering an antibody fusion protein comprising a murine single chain IL-12 (IL-12 beta subunit linked to the IL-12 alpha subunit) fused to an anti-Her2/neu antibody because Peng et al., 1999 (instant PTO-892) teaches an antibody fusion protein in which a murine single chain IL-12 (p40-linker-p35) (i.e. the IL-12 beta subunit linked to the IL-12 alpha subunit) is fused to an anti-Her2/neu antibody (antibody that targets a tumor associated antigen) at the amino terminus [page 251, left column, second paragraph], that the linker is a (Gly4Ser)3 flexible linker (peptide linker) [page 251, left column, last paragraph] and that CT26/Her2 mice were injected with the antibody fusion protein, which slowed the growth of tumors on day 1 and arrested tumor growth on day 6 (method of treatment for cancer) [page 255, left column, first paragraph].
With regard to the state of the art of treating all cancers with a single treatment, there is no known anticancer agent that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability. Bally (US 5,595,756) teaches that despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment-limiting toxicities” [column 1, lines 17-24].
HogenEsch et al., 2012 (instant PTO-892) teaches that there is no single cell culture or in vivo cancer model that faithfully predicts the efficacy of anticancer drugs in human clinical trials. Cell culture approaches offer the advantage of human-derived cell lines or tissue fragments from primary tumors, but cannot mimic the complexity of the reciprocal interaction between the growing tumor and the co-evolving microenvironment. Xenografts in immunodeficient mice have limited added value over cell culture models as the lack of an intact immune system and insufficient interactions between the human tumor cells and mouse stromal cells do not recapitulate human cancers [see page 6; Conclusion section]. Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
It is known in the art that cancer cells arising from different tissues differ in
etiology and response to treatment. Heppner and Miller, 1983 (instant PTO-892)
discuss the heterogeneity of tumors from different tissues and from the same tissue. Heppner and Miller teach that the heterogeneity of tumors contributes to the sensitivity the tumor will have to drugs [Summary, third paragraph]. Heppner and Miller further teach that as a tumor progresses to a metastatic phenotype, the way the tumor responds to treatment can differ, and thus, make it difficult to predict how the tumor will respond to the treatment [Page 15, right column, first paragraph].
Furthermore, Cooper, 2000 (instant PTO-892) teaches that cancer can result from abnormal proliferation of any of the different kinds of cells in the body [see Types of Cancer section]. Cooper further teaches that there are more than a hundred distinct types of cancer, which can vary substantially in their behavior and response to treatment [see Types of Cancer section].
Additionally, in regards to the present invention of a method of treating cancer comprising administering the generic chimeric protein to a patient, Tugues et al., 2014 (instant PTO-892) teaches that antitumor (cancer) treatments with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects [see Abstract]. Similarly, Lasek et al., 2014 (instant PTO-892) teaches that IL-12 is considered to be incapable of directly inhibiting cancer growth and that toxicities of IL-12 administration seem to prevail over its antitumor effectiveness [page 420, right column, first paragraph].
(6) the amount of direction or guidance presented; (7) the presence or absence of working examples:
There is a lack of working examples in the specification for treating all types of cancer with encompassed by the instant claims. The specification teaches that the binding specificity of a chimeric protein comprising HuIL-12 or MuIL-12 and the specific antibody named Hu51-4 was evaluated on Raji cancer cells (human Burkitt’s lymphoma cells) and that the chimeric protein did bind to the cells [see paragraph 77 of the specification]. However, the fact that this chimeric protein binds to a lymphoma cell does not necessarily mean it treats the cancer cell in any way. Applicant has not provided any substantive evidence of treating any cancer comprising administering a generic chimeric protein comprising an IL-12 portion and any cancer cell targeting portion, wherein the chimeric protein comprises in a single polypeptide sequence a single chain IL-12 comprising an IL-12α subunit and a IL-12β subunit coupled to each other via a peptide linker. Because the cancers encompassed by the instant claims are so disparate and no single cancer example can be representative of all the other encompassed cancers, a demonstration of support of a given condition does not provide support for the breadth of the claims.
Taken together, the art demonstrates that the treatment of cancer is highly unpredictable. Moreover, the art provides evidence that the heterogeneity of tumors contributes to the variability in treating cancer. Accordingly, it follows that cancers amenable to treatment with the claimed chimeric protein can only be identified empirically. This constitutes undue experimentation. Therefore, given the lack of guidance in the art, the lack of working examples commensurate in scope to the claimed invention and the unpredictability of treating cancer, the specification, as filed does, not provide enablement for the claimed genus of cancers.
Applying the above test to the facts of record, it is determined that 1) no declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record establishing the amount of experimentation necessary, 2) insufficient direction or guidance is presented in the specification with respect to broadly treating any cancer with the claimed antibody, 3) the relative skill of those in the art is commonly recognized as quite high (post-doctoral level). One of skill in the art would require guidance, in order to make or use the claimed antibody to treat the genus of cancers in a manner reasonable in correlation with the scope of the claims. Without proper guidance, the experimentation to is undue.
The Applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including all cancers. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, determining cancers that can treated with the claimed antibody, is unpredictable and the experimentation left those skilled in the art is unnecessarily and improperly, extensive and undue. See Amgen Inc v Chugai Pharmaceutical Co Ltd. 927 F 2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991) at 18 USPQ2d 1026-1027 and Exparte Forman, 230 U.S.P.Q. 546(Bd. Pat=. App & int. 1986).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph.
Claims 15 and 17, which depend from claim 14, are therefore rejected for the same reasons set forth above.
Claim 16 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 16 is drawn to a method of treatment for cancer in a patient in need thereof, the method comprising administration of an effective amount of a chimeric protein comprising an IL-12 portion and a cancer cell targeting portion; wherein the chimeric protein comprises in a single polypeptide sequence a single chain IL-12 comprising an IL-12α subunit and a IL-12β subunit coupled to each other via a peptide linker, wherein the cancer cell targeting portion targets a necrosis marker, and wherein the cancer cell targeting portion comprises an antibody heavy chain having the sequence of amino acids 539-991 of SEQ ID NO: 2 and an antibody light chain having the sequence of amino acids 24-236 of SEQ ID NO: 3. SEQ ID NOs: 2 and 3 appear to correspond to the antibody termed “Hu51-4” [see paragraph 76 of the instant specification].
The specification does not enable any method of treating cancer with this specific chimeric protein. The specification teaches that the binding specificity of the chimeric protein was evaluated on dead Raji cancer cells (human Burkitt’s lymphoma cells) [see paragraph 77 of the specification]. However, the fact that the chimeric protein binds to a lymphoma cell does not necessarily mean it treats the cancer cell in any way. Thus, the specification does not reasonably provide enablement for treating all cancers with this specific construct, as claimed in instant claim 16. 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.
Factors to be considered in determining whether undue experimentation is required, are set forth in In re Wands 8 USPQ2d 1400. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art and (8) the breadth of the claims.
(4) The nature of the invention and (8) The breadth of the claims:
The nature of the invention is a method of treating any cancer, comprising administering a specific chimeric protein (i.e. HuIL-12/Hu51-4 or MuIL-12/Hu51-4) to a patient. Therefore, the nature of the invention is a chemical case, where there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; see MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to practice the claimed methods, with a reasonable expectation of success, because it would not be predictable from the disclosure of any one particular species what other species may or may not work; see MPEP 2164.03.
The claims broadly encompass treating any cancer in a subject comprising administering the specific chimeric protein. Thus, the claims are broad in that they encompass treating any cancer. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body.
(5) The state of the prior art and (7) The predictability or unpredictability of the art:
While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regards to treating all cancers with a single treatment is underdeveloped. In particular, there is no known anticancer agent that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability. With regard to cancer treatment, Bally (US 5,595,756) teaches that despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment-limiting toxicities [column 1, lines 17-24].
HogenEsch et al., 2012 (instant PTO-892) teaches that there is no single cell culture or in vivo cancer model that faithfully predicts the efficacy of anticancer drugs in human clinical trials. Cell culture approaches offer the advantage of human-derived cell lines or tissue fragments from primary tumors, but cannot mimic the complexity of the reciprocal interaction between the growing tumor and the co-evolving microenvironment. Xenografts in immunodeficient mice have limited added value over cell culture models as the lack of an intact immune system and insufficient interactions between the human tumor cells and mouse stromal cells do not recapitulate human cancers [see page 6; Conclusion section]. Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
It is known in the art that cancer cells arising from different tissues differ in
etiology and response to treatment. Heppner and Miller, 1983 (instant PTO-892)
discuss the heterogeneity of tumors from different tissues and from the same tissue. Heppner and Miller teach that the heterogeneity of tumors contributes to the sensitivity the tumor will have to drugs [Summary, third paragraph]. Heppner and Miller further teach that as a tumor progresses to a metastatic phenotype, the way the tumor responds to treatment can differ, and thus, make it difficult to predict how the tumor will respond to the treatment [Page 15, right column, first paragraph].
Furthermore, Cooper, 2000 (instant PTO-892) teaches that cancer can result from abnormal proliferation of any of the different kinds of cells in the body [see Types of Cancer section]. Cooper further teaches that there are more than a hundred distinct types of cancer, which can vary substantially in their behavior and response to treatment [see Types of Cancer section].
Additionally, in regards to the present invention of a method of treating cancer comprising administering the specific chimeric protein to a patient, Tugues et al., 2014 (instant PTO-892) teaches that antitumor (cancer) treatments with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects [see Abstract]. Similarly, Lasek et al., 2014 (instant PTO-892) teaches that IL-12 is considered to be incapable of directly inhibiting cancer growth and that toxicities of IL-12 administration seem to prevail over its antitumor effectiveness [page 420, right column, first paragraph].
6) The amount of direction or guidance provided by the inventor; 7) The existence of working examples:
The specification teaches that the binding specificity of the specific chimeric protein was evaluated on dead Raji cancer cells (human Burkitt’s lymphoma cells) and that the chimeric protein did bind to these cells [see paragraph 77 of the specification]. Apart from a working example demonstrating that the claimed chimeric protein binds to lymphoma cells, the Applicant has not provided any substantive evidence of treatment of any cancer with the claimed chimeric protein. Because the cancers encompassed by the instant claims are so disparate and no single cancer example can be representative of all the other encompassed cancers, a demonstration of support of a given condition does not provide support for the breadth of the claims.
Taken together, the art demonstrates that the treatment of cancer is highly unpredictable. Moreover, the art provides evidence that the heterogeneity of tumors contributes to the variability in treating cancer. Accordingly, it follows that cancers amenable to treatment with the claimed chimeric protein can only be identified empirically. This constitutes undue experimentation. Therefore, given the lack of guidance in the art, the lack of working examples commensurate in scope to the claimed invention and the unpredictability of treating cancer, the specification, as filed does, not provide enablement for the claimed genus of cancers.
Applying the above test to the facts of record, it is determined that 1) no declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record establishing the amount of experimentation necessary, 2) insufficient direction or guidance is presented in the specification with respect to broadly treating any cancer with the claimed antibody, 3) the relative skill of those in the art is commonly recognized as quite high (post-doctoral level). One of skill in the art would require guidance, in order to make or use the claimed antibody to treat the genus of cancers in a manner reasonable in correlation with the scope of the claims. Without proper guidance, the experimentation to is undue.
The Applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including all cancers. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, determining cancers that can treated with the claimed antibody, is unpredictable and the experimentation left those skilled in the art is unnecessarily and improperly, extensive and undue. See Amgen Inc v Chugai Pharmaceutical Co Ltd. 927 F 2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991) at 18 USPQ2d 1026-1027 and Exparte Forman, 230 U.S.P.Q. 546(Bd. Pat=. App & int. 1986).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 14 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Peng et al., 1999 (instant PTO-892).
Regarding claims 14 and 15, Peng teaches an antibody fusion protein in which a murine single chain IL-12 (p40-linker-p35) (i.e. the IL-12 beta subunit linked to the IL-12 alpha subunit) is fused to an anti-Her2/neu antibody (antibody that targets a tumor associated antigen) at the amino terminus [page 251, left column, second paragraph] and that the linker is a (Gly4Ser)3 flexible linker (peptide linker) [page 251, left column, last paragraph]. Peng further teaches that CT26/Her2 (colon cancer) mice were injected with the antibody fusion protein, which slowed the growth of tumors on day 1 and arrested tumor growth on day 6 (method of treatment for cancer) [page 255, left column, first paragraph].
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 14, 15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Peng et al., 1999 (instant PTO-892), as applied to claims 14 and 15 above, in view of Munker et al., 2018 (instant PTO-892).
The teachings of Peng are above.
However, Peng does not specifically teach further administering low dose chemotherapy.
Regarding claim 17, Munker teaches a dose reduction of chemotherapy (low-dose chemotherapy) in patients with metastatic colon cancer due to side effects and that those with the dose reduction versus those with full dosage showed no significant different in overall survival, and that patients with N2 stage disease had improved survival with dose reduction [see Abstract].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered the low-dose chemotherapy as taught by Munker in combination with the antibody fusion protein of Peng in order to treat colon cancer in a patient in need thereof. One would have been motivated to have administered the low-dose chemotherapy in addition to the antibody fusion protein of Peng in order to treat colon cancer because both Munker and Peng each teach that these are known therapies to treat colon cancer. This follows the logic of MPEP 2144.06 which states “it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Therefore, it would have been obvious to combine the separate, known therapies for the same purpose of treating colon cancer.
Examiner’s Note
The Examiner considered the claims of 17/274,127 (now U.S. Patent No. 12,098,177; ‘177), which is the parent application to the instant application, and which teaches a chimeric protein that comprises an IL-12 portion and a cancer cell targeting portion, wherein the chimeric protein comprises in a single polypeptide sequence a scIL-12 in which an IL-12α subunit and a IL-12β subunit are coupled to each other via a peptide linker, and in which the scIL-12 is coupled to an N-terminus of the cancer cell targeting portion, and wherein the cancer cell targeting portion comprises an antibody heavy chain having the sequence of amino acids 539-991 of SEQ ID NO: 2, and an antibody light chain having the sequence of amino acids 24-236 of SEQ ID NO: 3.
SEQ ID NOs: 2 and 3 of ‘177 are 100% identical to SEQ ID NOs: 2 and 3 as claimed in instant claim 16.
However, since instant claim 16 is not enabled for a method of treating cancer, no double patenting rejection was made.
Further, the tables below indicate the residues searched for each of the CDRs within SEQ ID NO: 2 of the heavy chain of the hu51-4 antibody and SEQ ID NO: 3 of the light chain of the hu51-4 antibody according to Kabat and IMGT numbering:
Table 1: Residues searched for SEQ ID NO: 2
Kabat
IMGT
CDR-H1
Residues 571-575
Residues 566-573
CDR-H2
Residues 590-606
Residues 591-598
CDR-H3
Residues 639-650
Residues 637-650
Table 2: Residues searched for SEQ ID NO: 3
Kabat
IMGT
CDR-L1
Residues 46-56
Residues 49-54
CDR-L2
Residues 72-78
Residues 72-74
CDR-L3
Residues 111-119
Residues 111-119
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Brittney E Donoghue whose telephone number is (571)272-9883. The examiner can normally be reached Mon - Fri 7:30 - 3:30.
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/B.E.D./Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
