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 Application, Amendments and/or Claims
The amendment, filed 08 September 2023, has been entered in full. The amendment, filed 08 December 2023, has been entered in full. The amendment, filed 01 February 2024, has been entered in full. Claims 1-20 are under examination.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 02 July 2024) was received and complies with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. It has been placed in the application in file and the information referred to therein has been considered as to the merits.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description: The Brief Description of the Drawings recites 6A, but the actual drawing for Figure 6 does not recite 6A.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 15 is objected to because of the following informalities: Claim 15 is missing a period. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) 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.
Claims 1-20 are 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.
Claims 1, 9 and 19 are indefinite because of the recitation, “..a molecule capable of binding to an epidermal growth factor receptor (EGFR) in a cell..”
Claims 3 and 11 are indefinite because of the recitation, “...molecule is capable of inhibiting migration driven by a second receptor tyrosine kinase (RTK)..”
The claims are indefinite because the word “capable” just means “having the ability”. However, it is unclear if the molecule actually “binds to an EGFR in a cell” or actually “inhibits migration driven by a second RTK”.
Claims 2, 4-8, 10, 12-18 and 20 are included in this rejection insofar as they depend from claims 1, 9 and 19 and do not resolve the issue discussed above.
Claim 15 is indefinite because of improper antecedent basis. See claim 15, line 1, which recites , “...wherein the dosage..”. Claims 10 and 9, from which claim 15 depends, do not recite a dosage limitation.
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.
Claims 9-18 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 for treating breast cancer in a subject
does not reasonably provide enablement for:
A method for treating any/all cancers in a subject OR
A method for treating all EGFR-dependent cancers in a 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/or use the invention commensurate in scope with these claims.
The specification teaches that hormone receptor negative breast cancer represents approximately 40% of all breast cancer cases and is the most aggressive and metastatic. Triple-negative breast cancer is cancer that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein. The specification teaches that the HER family of tyrosine kinase receptors (RTKs, including EGFR, HER2 and HER3) is highly prevalent in breast cancer, and in some cases, antibody-based therapeutics against these tyrosine kinase receptors (i.e., Trastuzumab) are effective. However, in HER2 negative, but EGFR and HER3 positive breast cancer, antibody-based treatments have not shown efficacy. In addition, while Tyrosine Kinase Inhibitors (TKIs) work well in many cancers, such as
lung, head and neck and colon cancer, they have failed to be impactful in breast cancer.
The specification teaches targeting of EGFR and other RTKs has historically focused on two areas: either with small molecule inhibitors of the tyrosine kinase activity (TKIs), or via specific antibodies that bind to the cell surface-localized receptor to either alter receptor activation, induce its internalization and degradation, or to activate the patient's immune system against antibody-bound cells. While these approaches have had stunning success in certain types of cancers, such as HER2 positive breast cancer and EGFR-positive lung cancer, they have failed to impact EGFR-expressing breast cancers. Cancers caused by other oncogenic receptors such as the Met receptor and HER3 also respond poorly to such therapeutics.
The specification teaches that in HER2 negative, but HER1 or HER3 positive cases, HER-targeted treatments are ineffective. HER1 is not found on the cell surface, but instead is localized to the nucleus. HER1/EGFR can undergo retrotranslocation (rt-EGFR) to long-lived intracellular vesicles and the nucleus, where it can both continue to signal and act directly as a transcriptional cofactor. It has been shown that in certain breast cancer cells, activated EGFR receptors can
undergo retrograde trafficking (Retrograde Trafficked EGFR; rt-EGFR) and reside intracellularly instead of on the cell surface where it may be targeted by antibody-based therapeutics. In this way, EGFR is maintained in long-lived endosomes that do not get targeted to the lysosome for degradation, and also undergoes nuclear translocation where it functions directly as a transcriptional cofactor. Once in the nucleus, EGFR may function as a transcriptional cofactor regulating the expression of genes that promote proliferation, survival and stemness. Rt-EGFR is correlated with metastatic progression, patient mortality and therapeutic resistance and may regulate the expression of a number of oncogenes that drive metastasis and survival.
The present disclosure provides compositions and methods for treating breast cancer. It is disclosed that cancer-specific trafficking event can be therapeutically targeted, which results in inhibition of nuclear retrotranslocation of EGFR and other similarly regulated RTKs, such as HER3 and c-Met.
The Examples teach that certain sorting nexin (SNX) peptides can inhibit cell viability in MDA-MB-468 triple negative breast cancer cells. The Examples teach that administered cSNX1.3 peptide promoted tumor regression in WAP-TGF alpha mice. This mouse model forms mammary adenocarcinomas. The Examples teach cSNX1.3 inhibits tracking of EGFR to the nucleus and signaling from endosomes.
The claims are not enabled for the full scope for the following reasons:
1. Regarding treating all types/forms of cancer: Given the guidance from the instant specification, one of ordinary skill in the art could reasonably predict that administering cSNX1.3 would be useful in methods of treating breast cancer.
However, the specification fails to teach that all types of cancer can be treated with cSNX1.3. Cancer encompasses diverse diseases such as brain cancer, colon cancer, multiple myeloma, ovarian cancer, leukemia or skin cancer. These cancers have very different pathologies and etiologies. The specification establishes no connection between any of these diverse cancers and cSNX1.3.
See wherein Hassanpour et al. teach that cancer in the broader sense refers to more than 277 different types of cancer disease. Hassanpour et al. teach that cancer is a variety disease at the tissue level. Hassanpour et al. teach that this variety is a major challenge for its specific diagnosis, followed by efficacy of treatment. Hassanpour et al. teach scientists have stated several gene mutations are involved in cancer pathogenesis; also included are chemical compounds, environmental chemical substances with carcinogenic properties, viruses, bacteria and radiation rays. The art teaches that a host of molecules, factors, and conditions have been designated as underlying causes for the inception and progression of cancer (Hassanpour et al. Review of cancer from perspective of molecular. Journal of Cancer Research and Practice. Volume 4:127-129; available July 2017).
2. Regarding treating all types/forms of EGFR-dependent cancers: See wherein Jameson et al. teach that EGFR is frequently overexpressed in a variety of cancer types, including cancers of the head and neck (HNSCC) and glioblastoma (GBM). Jameson et al. teach that overexpression of EGFR is detectable in as much as 84% of HNSCC tumors, with mutation and/or amplification occurring in approximately 31% of these tumors. Jameson et al. teach that glioblastoma possesses a stronger correlation between EGFR copy number and expression, with mutation and/or amplification occurring in approximately 46% of GBM, over 90% of which overexpress the protein. Jameson et al. teach that recent large-scale analysis of cancer epigenomes identified a significant relationship between somatic copy-number alterations (SCNA) and enhancer expression, with the most significant increases in enhancer expression occurring in tumors that have high aneuploidy and high mutation load. Jameson et al. teach that HNSCC and GBM have high SCNA frequency and a high frequency of EGFR gene alterations, indicating epigenome hyperactivity may play a role in overexpression of EGFR (page 2208)(Jameson et al. Intron 1–Mediated Regulation of EGFR Expression in EGFR-Dependent Malignancies Is Mediated by AP-1 and BET Proteins. Mol Cancer Res; 17(11):2209-2220; November 2019).
However, the instant specification teaches cSNX1.3 had no effect on cell line H1975, which has an EGFR driver mutation in the kinase domain. The specification teaches that cSNX1.3 peptide is highly selective toward cancers expressing wildtype EGFR. Based on the teachings of Jameson, many EGFR-dependent cancers have mutations in the EGFR. It could not be predicted that SNX1.3 peptide could be employed to treat all EGFR-dependent cancers.
3. Most importantly, the specification lacks appropriate animal models for the breadth of treating all cancers (or EGFR-dependent cancers): The instant specification teaches the use of an animal model for mammary adenocarcinomas (WAP-TGF alpha mice). This particular animal model would not be correlative with discerning therapeutic agents for in vivo treatment of other cancers. The results of cSNX1.3. in an animal model for breast cancer would not be predictive of treating bone cancer.
See wherein Justice et al. teach, “It seems an obvious point, but the model used should be appropriate for the question being addresses. An ideal disease model accurately mimics the human condition, genetically, experimentally and/or physically”. Justice et al. teach that in one example, data from human blunt-trauma patients were analyzed together with data from a mouse inbreed strain that had been exsanguinated. Justice et al. teach, “Losing a large amount of blood does not equate to blunt trauma, and so this could be perceived as comparing apples to oranges” (page 101, 2nd column 2nd full paragraph). Justice et al. teach that in a different study, a mouse model was reported to display the key motor symptoms seen in humans with amyotrophic lateral sclerosis (ALD). On the basis of this, the model was used in preclinical trial studies and promising drugs candidates were tested in clinical trials; however the drugs ultimately failed in humans. It was show that the particular mouse is a poor genetic and phenotypic model of human conditions. Justice et al. state, “This example illustrates how relevance to the human disease being studied, supported by strong data to validate the use of the model is crucial for clinical translation” (page 102, left column, 1st full paragraph)(Justice et al. "Using the mouse to model human disease: increasing validity and reproducibility, Disease, Models & Mechanisms 9:101-103, 2016).
It cannot be said that the specification provides the necessary guidance for treating all cancers or all EGFR-dependent cancers. The skilled artisan would accordingly have no resort save trial-and-error experimentation to determine which cancer patient population can be treated with cSNX1.3. Such experimentation would be undue. The specification provides insufficient guidance with regard to these issues and provides no working examples which would provide guidance to one skilled in the art. No evidence has been provided which would allow one of skill in the art to predict the efficacy of the claimed methods with a reasonable expectation of success.
Due to the inherent unpredictability and the large quantity of experimentation necessary to treat all forms of cancers or all EGFR-dependent cancers; the lack of direction/guidance presented in the specification regarding same; the absence of working examples directed to same; the complex nature of the invention; the state of the art which establishes the use of appropriate animal models to discern in vivo treatments and the breadth of the claims which fail to limit cancer diseases that can be effectively treated in a subject; undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Claims 1-6, 9-12, 15-19 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.
The instant claims are not supported by an adequate written description. A molecule is required to practice the claimed invention. The molecule must have the biological function of “binding to an epidermal growth factor receptor (EGFR) in a cell AND inhibits retrotranslocation of the EGFR to the nucleus of the cell AND binds the kinase domain of the EGFR AND inhibits migration of a second receptor tyrosine kinase (RTK) , wherein the second RTK is different from EGFR AND treats all cancers when administered to a subject”.
The instant claims encompass a genus of undisclosed molecules based entirely on function. The encompassed genus of molecules have functional limitations, but no structural limitations. The genus includes vastly structurally diverse molecules such as peptides, polypeptides, chemical analogs, lipids, antibodies, nucleic acids, organic molecules, inorganic molecules, etc. The number of structures encompassed by the genus may be vast or conversely there may be no structures that possess the claimed function.
MPEP§ 2163 states that the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (show a structure is correlated with the function) OR through a sufficient description of a representative number of species (show a representative number of species that have the function. There must be enough species that are representative of the full breadth of the genus).
As was stated above, the genus encompasses molecules such as antibodies. The scientific literature recognizes that the formation of an intact antigen-binding site of all antibodies requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (see entire reference)(Al Qaraghuli et al. Antibody‑protein binding and conformational changes: identifying allosteric signaling pathways to engineer a better effector response. Nature Scientific Reports 10:13969, 2020).
Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences, and representative of almost the entire extensive heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines), and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (see entire reference)(Edwards et al. The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS. Journal of Molecular Biology 334:103-118; 2003). Thus, a single protein can be bound by a very large and structurally diverse genus of antibodies (i.e., there is no common structural relationship even for antibodies that bind to the same protein, epitope, or overlapping epitopes).
Goel et al. teach that three mAbs that bind to the same short (12-mer) peptide, exhibit diverse V gene usage, indicating their independent germline origin. Said reference further teaches that two of these mAbs recognize the same set of amino acid residues defining the epitope (alternate amino acid residues spread over the entire sequence), however, the relative contribution of each set of residues in the peptide showed significant variation. The reference notes that all of the mAbs do not show any kind of V gene restriction among themselves, implying variable paratope structure, despite that two of these mAbs bind to the peptide through a common set of residues. (See entire reference)(Goel et al. Plasticity within the antigen-combining site may manifest as molecular mimicry in the humoral immune response. J. Immunol. 173: 7358-7367; 2004).
The genus encompasses molecules such as peptides and polypeptides. The scientific literature recognizes that the problem of predicting protein structure and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex. It is in no way predictable that randomly selected changes in a disclosed sequence would afford a peptide or polypeptide having activity comparable to the one disclosed.
For sequences having one or two substitutions, for example, the artisan would reasonably expect that many of the possible variants would retain functional properties comparable to those of the unmodified protein, and it would require only routine manipulations to make and test a reasonably representative sampling of the possible variants. However, as the number of modified sites increases, the number of possible variants, and hence the degree of experimentation required, increases exponentially. Additionally, as plural substitutions are introduced, their interactions with each other and their effects on the structure and function of the protein become progressively less predictable.
Even if the instant specification outlined art-recognized procedures for producing and screening for active muteins, this is not adequate guidance as to the nature of active derivatives that may be constructed, but is merely an invitation to the artisan to use the current invention as a starting point for further experimentation. The ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active; conformation is dependent upon surrounding residues. Substitution of non-essential residues can often destroy activity
For example, Fenton et al. state that while it is well known that most substitutions at conserved amino acid positions (which they call “toggle” switches) abolish function, it is also true that substitutions at non-conserved positions (which they call “rheostat” positions) are equally capable of affecting protein function. They conclude that substitutions at rheostat positions have highly unpredictable outcomes on the activities and specificities of protein-based drugs (see entire reference)(Fenton et al. Rheostat positions: A new classification of protein positions relevant to pharmacogenomics Medicinal Chemistry Research 29:1133-1146; 2020).
Bhattacharya et al. state that the range of possible effects of even single nucleotide variations at the protein level are significantly greater than currently assumed by existing software prediction methods, and that correct prediction of consequences remains a significant challenge (p. 18)( Bhattacharya et al. Impact of genetic variation on three dimensional structure and function of proteins PLoS ONE 12(3): e0171355; 2017). See also Tokuriki et al. (Stability effects of mutations and protein evolvability, Current Opinion in Structural Biology, 19:596-604, 2009).
In addition, when multiple mutations are introduced, there is even less predictability. As the number of modified sites increases, the number of possible variants, and hence the degree of experimentation required, increases exponentially. As plural substitutions are introduced, their interactions with each other and their effects on the structure and function of the protein become progressively less predictable. For evidence thereof, see Guo et al., who state that the effects of mutations on protein function are largely additive (page 9207, left column, full paragraph 2)(Guo et al. Protein tolerance to random amino acid change. PNAS USA 101(25):9205-10; 2004).
The state of the prior art evidences the unpredictability of the effects of mutation on structure and function.
Regarding a representative number of species: The instant specification fails to describe a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163.
The instant specification teaches about 20-25 sorting nexin (SNX) peptides, wherein 3 peptides demonstrated less than 50% cell viability of MDA-MB 468 breast cancer cells in vitro and wherein 1 peptide is shown to have the required functions recited in the claims such as inducing tumor regression in an animal model for mammary adenocarcinoma (i.e. SNX1.3). The specification teaches SNX1.3 as comprising SEQ ID NO:1 and SEQ ID NO:2 is the sequence of SEQ ID NO:1 wherein the N-terminal end is acetylated (CH3CO) and the C-terminal end is amidated (CONH2).
The disclosure is not representative of the claimed genus, which includes chemical analogs, lipids, antibodies, nucleic acids, RNA, organic molecules, inorganic molecules and any non-structurally defined moiety having the required function encompassed by the claims. There is substantial variation within the genus and the instant specification fails to describe a sufficient variety of species to reflect the variation within the genus. There must be enough species that are representative of the full breadth of the genus.
The claims depend on a recited property, where the claim covers every conceivable structure for achieving the stated property, while the instant specification fails to describe any species with sufficient identifying characteristics such that one skill in the art could visualize or recognize the identity of the claimed subject matter. The specification fails to teach the structural identifying characteristics that are applicable to the genus. The skilled artisan cannot envision the detailed chemical structure of the encompassed claimed molecules (if any) which have the activity without further testing, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification.
The courts have specifically stated that the skilled artisan cannot envision the detailed chemical structure of an encompassed polypeptide until the structure is disclosed, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. §112, first paragraph.
Conclusion
No claims are allowed.
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/R.M.D/Examiner, Art Unit 1647 2/18/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647