DETAILED ACTION
Claim Status
As of the Non-Final Office Action mailed 8/21/2025, claims 1-6, 8, 12, 14, 16-18, 31-34, 37-39, 42, and 48 were pending and claims 1-6, 8, 12, 14, 16-18, and 48 were withdrawn for being drawn to nonelected invention.
In Applicant's Response filed on 2/23/2026, claims 31, 34, 37 were amended, claim 32 was canceled and claim 66 was newly added.
As such, claims 1-6, 8, 12, 14, 16-18, 31, 33-34, 37-39, 42, 48, and 66 are pending and claims 31, 33-34, 37, 39, 42, and 66 have been examined herein.
Withdrawn Objections/Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections or rejections not specifically reiterated are hereby withdrawn.
Claim Rejections - 35 USC § 112(a) – Necessitated by Amendment
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.
Scope of enablement
Claims 31, 33-34, 37, 39, 42, and 66 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabled for 1) “ameliorating one or more clinical indicia of disease activity and ameliorate undesired symptoms” associated with melanoma or breast cancer AND enabled for a method of 2) ameliorating clinical indicia of disease activity and undesired symptoms of melanoma in an immunocompetent subject, the method comprising the step of administering to said subject via intramuscular immunization an sgRNA wherein said sgRNA targets 3’ or 5’ splice sites of exon 4 of tyrosinase gene OR 3) ameliorating clinical indicia of disease activity and undesired symptoms of breast cancer in an immunocompetent subject, the method comprising the step of administering to said subject via intramuscular immunization an sgRNA wherein said sgRNA targets 3’ splice site of exon 6 of heterogeneous nuclear ribonucleoprotein A/B, does not reasonably provide enablement for “prevent the manifestation of undesired symptoms before they occur”, “prevent disease from occurring”, “slowing the development of a neoplastic disorder,” and inhibiting or preventing all other cancerous or noncancerous neoplastic disorders in all other subjects utilizing all other splicing modulating agents comprising all other nucleic acid sequence, or vector, vehicle, matrix, nanoparticle, microparticle, or composition comprising said agent administered via all other administration routes embraced by the claims. 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 pending instant claims have been amended, claim 32 was canceled and claim 66 is newly added; the rejection is recast and modified, however, most of the substantive points remain unchanged as posited in the Non-Final Office action mailed 8/21/2025.
While determining whether a specification is enabling, one considered whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirement, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d at 737, 8 USPQ2d 1400, 1404 (Fed. Cir.1988)).
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore, skepticism raised in the enablement rejection are those raised in the art by artisans of expertise.
Nature of the invention:
A method for treating, inhibiting, or ameliorating at least one neoplastic disorder in a subject, wherein said neoplastic disorder is a malignant neoplastic disorder, the method comprising the step of: administering to said subject at least one splicing modulating agent comprising at least one nucleic acid sequence, or of any vector, vehicle, matrix, nano- or micro-particle or composition comprising said at least one agent, wherein said at least one nucleic acid sequence of said agent targets at least one target nucleic acid sequence that participates directly or indirectly in at least one splicing event of a target gene; wherein introduction of said agent into said target cell in said subject induces at least one aberrant splicing event via said target nucleic acid sequence; and wherein said aberrant splicing event results in the production of at least one neoantigen expressed by said target cell, thereby activating an immune response directed against said target cell in said subject; wherein said splicing modulating agent comprises at least one of: (a) at least one oligonucleotide comprising a nucleic acid sequence complementary to at least part of said target nucleic acid sequence; and (b) at least one nucleic acid sequence comprising at least one guide RNA that targets at least one protospacer within said target nucleic acid sequence, or any nucleic acid sequence encoding said gRNA, said gRNA guides at least one programmable engineered nuclease (PEN) to said target nucleic acid sequence in said target gene; and wherein said at least one target nucleic acid sequence that participates directly or indirectly in at least one splicing event is comprised within at least one coding transcript characterized by at least one of: (i) said coding transcript comprises at least three exons; (ii) at least one of said exons is of a length not divisible by three; and (iii) the coding transcript comprises at least one intron.
The state of the prior art:
The state of the prior art for treating, inhibiting, or ameliorating at least one neoplastic disorder in a subject by administering any splicing modulating agent via various administration routes was unpredictable before the effective filing date of the claimed invention.
The breadth of the claims:
The claims encompass using a splicing modulating agent comprising any nucleic acid sequence, or any vector, vehicle, matrix, nanoparticle, microparticle, or any composition containing the agent via various administration routes to treat, inhibit, or ameliorate neoplastic disorders in various subjects. Various malignant neoplastic disorders include leukemia, lymphoma, melanoma, prostate cancer, lung cancer, breast cancer, ovarian cancer, renal cell carcinoma, pancreatic cancer, gliomas, hepatocellular carcinoma, hemangiomas, adenomas, etc. Various administration routes include direct injection, subcutaneous, intravenous, intramuscular, intrathecal, intraperitoneal, oral, topical, dermal, transdermal, inhalation, intranasal administration, etc. The instant claims embrace treating , ameliorating, or inhibiting any neoplastic disorder in a subject (may or may not have any neoplasms). The instant claims embrace administering to immunocompetent and immunodeficient subjects.
The specification defines “treating” to include ameliorating one or more clinical indicia of disease activity by administering a pharmaceutical composition of the invention in a patient having a pathological disorder and administering of a therapeutic amount of the composition which is effective to ameliorate undesired symptoms associated with a disease, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, or to improve survival rate or more rapid recovery, or a combination of two or more of the above (p. 79). The specification also defines "amelioration" as relating to a decrease in the symptoms, and improvement in a subject's condition (same page). The term "inhibit" is defined to encompass the restriction or prohibition of the progress and exacerbation of pathologic symptoms or a pathologic process progress.
The World Health Organization (Global Forum IV on Chronic Disease Prevention and Control, Nov 2004) defines prevention as “approaches and activities aimed at reducing the likelihood that a disease or disorder will affect an individual, interrupting or slowing the progress of the disorder or reducing disability” (p. 50). It also describes three types of prevention: 1) primary (which reduces the likelihood of the development of a disease or disorder), 2) secondary (which interrupts, prevents, or minimizes the progress of a disease at an early stage), and 3) tertiary (which focuses on halting the progression of damage already done).
There is overlap between the definition provided in the specification for “treating,” and “inhibiting,” and what is known in the art as tertiary prevention/preventative measures. As such, the breadth of the claims as it relates to “treating” and “inhibiting” of a neoplastic disorder encompasses prevention of neoplastic disorders.
The level of skill in the art:
The level of skill is high that requires a researcher with a PhD degree.
The working examples and guidance provided:
The specification discloses working examples in which tyrosinase is examined as a potential target for aberrant induced splicing in melanoma (example 2), induction of novel isoforms of tyrosinase by inducing the exclusion of exon 4 from tyrosinase (example 3), vaccination with immunogenic TYP peptide in C57BL/6 mice and use of CRISPR/cas system to target exon 4 (examples 4 and 5). Example 6 describes splicing modulation of tyrosinase using CRISPR/cas does not affect the cancerous properties of melanoma cells. Example 7 describes that tyrosinase splicing modulation with CRISPR/cas inhibits tumor growth in immunocompetent but not in immune-deficient mice. Example 8 describes immunization of C57BL/6 mice with TYR peptides then injection with melanoma cells having TYR splicing modulation by CRISPR/cas. Example 9 describes evaluation of the effect of TYR splicing modulation by oligonucleotides designed for TYR exon4 skipping into C57BL/6 mice. Example 10 describes that HNRNPAB gene is overexpressed in multiple human cancers and aberrant splicing of its exon6 leads to formation of potentially immunogenic peptides. Example 11 describes hnRNPAB splicing modulation with CRISPR/cas9 results in a new isoform of hnRNPAB. Example 12 describes hnRNPAB splicing modulation with CRISPR/cas9 in 4T1 cells inhibits tumor growth in BALB/c mice but not in immune-deficient (NOD-SCID) mice. Example 13 describes the immunization of BALB/c mice with aberrant hnRNPAB peptides followed by injection of 4T1 breast cancer cells containing hnRNPAB splicing modulation by CRISPR/cas9. Example 14 describes identification of target sequences for aberrant splicing in transcripts overexpressed in cancers.
The specification fails to provide any working examples (in vitro, in vivo, or prophetic) in which any benign or any other malignant neoplasm (other than melanoma and breast cancer) embraced by the claims is treated/prevented/inhibited using the splicing modulating agent of the instantly claimed method nor any adequate guidance and evidence to treat/prevent any other such diseases using a nucleic acid sequence generally.
The specification fails to provide adequate guidance and evidence for how to administer a nucleic acid via various administration routes other than intramuscular injection to treat/prevent/inhibit any benign neoplasms or any other malignant neoplasms other than melanoma and breast cancer.
The unpredictable nature of the art:
The claims encompass using various splicing modulating agent (i.e., gene therapy) to treat (which encompasses prevention), ameliorate, or inhibit (which encompasses prevention) various cancerous and benign neoplastic disorders in various subjects via various administration routes. Various cancerous and benign neoplastic disorders include leukemia, lymphoma, melanoma, prostate cancer, lung cancer, breast cancer, ovarian cancer, renal cell carcinoma, pancreatic cancer, gliomas, hepatocellular carcinoma, fibroids, lipomas, moles, hemangiomas, adenomas, etc. Various splicing modulating agents include nucleic acid sequences comprising various DNAs, RNAs, as well as various vectors, vehicles (such as cells), matrices, nanoparticles, microparticles, and general compositions containing the various nucleic acid sequences. Various subjects include immunocompetent and immunodeficient subjects. The state of the art of using gene therapy (nucleic acid sequences and those contained within vectors vehicles matrices nano- and micro-particles) to treat/prevent, ameliorate, and inhibit various cancerous and benign neoplastic disorders in immunocompetent and immunodeficient subjects was unpredictable before the effective filing date of the claimed invention.
Prevention of neoplastic disorders:
Neoplastic disorders cannot be prevented. According to Cleveland Clinic’s website (“Benign Soft Tissue Tumors”, 3/29/2023, retrieved 18 February 2025), most benign soft tissue tumors, such as lipomas, hemangiomas, and fibromas cannot be prevented (p.2 and 9). According to the CDC’s website (“Preventing Cancer”, 16 Jan 2025, retrieved 15 Feb 2025), the risk of getting many common kinds of cancers can be lowered by making healthy choices, using screening tests to find cancers early, and the use of vaccines to help prevent certain kinds of cancers (such as HBV-induced hepatocellular carcinoma which can develop after HBV infection; the vaccination helps prevent HBV resulting in prevention of HBV-induced hepatocellular carcinoma). There is no one modality that can “prevent” any and all cancerous and benign neoplastic disorders.
Treatment of various cancers:
The claims read on ameliorating symptoms of various malignant neoplasms including leukemia, lymphoma, melanoma, prostate cancer, lung cancer, breast cancer, ovarian cancer, renal cell carcinoma, pancreatic cancer, gliomas, hepatocellular carcinoma, lipomas, hemangiomas, adenomas, etc. No one treatment modality can ameliorate symptoms of all malignant neoplasms.
Cancer therapy is highly unpredictable, and no example exists for the efficacy of a single product against all cancers generally. Environmental factors and genetics are just some of the variables that affects disease development and treatment response. The National Cancer Institute, in their webpage about cancer treatment (retrieved 15 Feb 2025), states that the types of treatment for cancer depends on the type of cancer you have and how advanced it is. Some people with cancer only have one treatment, but most people require a combination of treatments, including chemotherapy, surgery, radiation therapy, immunotherapy, targeted therapy, and hormone therapy. This shows that a singular treatment cannot be the “end-all, be-all” for cancer.
Cote et al (2021, Ch. 1 Epidemiology and Etiology of Glioblastoma; Precision Molecular Pathology of Glioblastoma; p. 3-19), for example, teaches the epidemiological feature of glioblastoma. Glioblastomas are the most common primary brain malignancy and overall are rare compared to other malignancies. Despite intensive research, survival rates for glioblastoma have remained relatively unchanged with the treatment protocol outlined in the “Epidemiological Features of GB” section (p. 5 para 1). Current survival rates are approximately 40% for 1 year and a 5-year relative survival of about 5% (p. 5 para 1). There are substantial differences in the incidence of glioblastoma by race and ethnicity and there are many potential risk factors that potentially contribute to individual risk of developing glioblastoma including ionizing radiation exposure (p. 6, “Etiology of Glioblastoma”). Specifically, Cote shows that there are 11 common genetic variants affecting risk for glioblastoma in European adults and “the proportion in incidence variance of GB attributable to genetic factors in estimated to be 26%” with “73% of the genetic risk currently unexplained” (see p. 12 “Common Genetic Variants in Adult GB” and Table 1.2). There is no indication that a change in one risk factor (such as via gene therapy) would prevent the development of glioblastoma.
Gene therapy and administration routes:
Durymanov et al (Front Pharmacol. 2018 Aug 21; 9:971) states that cancer gene therapy remains a significant challenge due to numerous barriers limiting delivery of genetic cargo (Introduction para 1). Multiple physiological barriers upon systemic administration remain a key challenge in clinical translation of anti-cancer gene therapeutics (abstract). Besides extracellular barriers including sequestration of gene delivery nanoparticles from the bloodstream by resident organ-specific macrophages, and their poor extravasation and tissue penetration in tumors, overcoming intracellular barriers is also necessary for successful delivery of nucleic acids (same para). Nanoparticles for nucleic acid delivery have to reach the specific intracellular compartment; either cytosol for siRNA and mRNA, or nucleus in case of DNA (Introduction para 1). While synthetic carriers can form complex with nucleic acids and are considered an alternative to viral vectors, engineering of non-viral carriers requires great effort to rationally design nucleic acid nanoformulations to overcome cellular barriers (Introduction para 2). Development of cationic polymers and lipids with their ability to deliver genetic material into cells has given rise to extensive studies of the mechanisms underlying transfection properties of these carriers however the progress in this direction is still insufficient (same para). Aspects of nanoparticle tuning for in vivo translation are contradictory to transfection efficacy on a cellular level because, while positive charge of the nanocarrier protects genetic cargo form extracellular nucleases, facilitates interaction with the cell surface and uptake, and provides endosomal escape by interaction with anionic phospholipids in endosomal membrane, the positive surface charge may also cause fast elimination of nucleic acid nanoformulations from circulation and off-target delivery of nucleic acids (p. 11, para 1). Using neutral hydrophilic polymer (such as PEG) for nanoparticle shielding for intravenous administration extends circulation time and improves diffusion-mediated permeation of tumor stroma due to minimization of electrostatic interactions with extracellular matrix, but functionalization with PEG impairs cellular uptake and may reduce endosomal escape efficacy (same para). The efficacy of lipid nanoparticles endosomal escape and cellular uptake are not very high and require additional optimization (same para). Furthermore, clinically relevant mitosis-independent mechanisms of DNA translocation into the nuclei of cancer cells are unknown, ineffective, and not well-managed (Conclusion, para 1). For RNA delivery, the endosomal barrier holds a key importance. Administration routes also play an important role to determine whether sufficient RNA can be obtained at the target sites in a subject. Different administration routes of nucleic acids can result in different efficiency of gene expression and can influence whether sufficient expressed gene product can be obtained at the target cells to perform its purpose in vivo.
Post-dated Aljabali et al (Int J Mol Sci. 2023 Jan 19; 24(3):2008) states that sheer quantity of physicochemical properties of nanoparticles (NPs), including shape, size, morphology, and elemental constituents, makes the investigation of their cytotoxicity consequences complex and challenging. Oxidative stress, inflammation, genetic damage, cell division, and cell death suppression are paradigms for NP-mediated toxicity (“Nanomaterials and Immune System Modulations”, para 1). Nanoparticle-mediated ROS responses orchestrate a cascade of adverse pathological processes such as inflammation, genotoxicity, fibrosis, and carcinogenesis (“Nanomaterials and Immune System Modulations”, para 3). When used in vivo, NPs and the interface between the NP and the biological material play a key role in how the nanomaterial is transported, eliminated, and deposited, especially when it comes to the systemic administration of medicines (“Immunological Effects of Nanomaterials”, para 1). When the immune system encounters a foreign body, such as NPs, the first cells to respond are phagocytic cells. There have been several reports of negative interactions between the immune system and nanoparticles, with immune stimulator immunosuppression potentially leading to inflammatory or autoimmune diseases and increasing the receptor likelihood that the body will get infected. Almost all the immunostimulatory responses elicited by nanoparticles are mediated by the release of pro-inflammatory cytokines. Numerous studies have provided evidence through various forms of nanomaterials that can induce cytokine production, i.e., AuNPs, lipid-based NPs, dendrimers, etc. (“Immunostimulant”, para 3). Lipid-based NPs, polymeric NPs, metal-based NPs, silica NP, and carbon nanotubes are examples of NPs drug delivery systems, and while they have had rapid and successful use as delivery system, it is accompanied by limited knowledge about their anticipated toxicity and immunity (“Interactions with the Immune System” para 2).
Vector gene therapy:
Kotterman et al. (2014 Nature Reviews, Vol. 15, p. 445-451) reports that AAV still has significant challenges regarding successful use in treatment regimens (pg. 450 col. 2). Specifically Kotterman points out widespread natural exposure to AAVs has resulted in a large portion of the population with neutralizing antibodies specific to capsids in the blood and other body fluids, which markedly limit gene delivery by many natural vectors... following cellular transduction, AAV capsid epitopes can become cross-presented on major histocompatibility complex (MHC) class I molecules, which leads to the elimination of transduced cells by capsid-specific cytotoxic T lymphocytes and the corresponding loss of gene expression. For systemically administered viruses, the liver is often the default destination, which can represent a barrier when other organs are the intended targets. In addition, endothelial cell layers, especially those within the blood-brain barrier, pose a physical barrier for entry into a tissue. A vector that gains access to an organ, or that is directly administered to that organ, can then encounter numerous transport barriers to efficient transduction of the often-large tissue volumes involved in disease, including cell bodies and intervening extracellular matrix to which many AAV variants bind. The surface of a target cell may lack the primary and/or secondary receptors that are necessary for vector binding and internalization. Furthermore, endosomal escape, proteasomal escape, nuclear entry and vector unpackaging all represent barriers to transduction" (e.g. p. 447, under BOX 1).
Shim et al. (2017, Current Gene Therapy, Vol. 17, No. 5, p. 1-18) reports that in all gene therapy applications, delivery issues are essential, and nucleic acids are highly polar macromolecules and cannot diffuse through cell membranes. For the delivery of nucleic acids into target cells, viral and nonviral methods have been used. Despite success, viral vectors still suffer from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems (e.g. p. 1, right column, 2nd paragraph). Although nonviral methods have many advantages, including safety, the reasons these methods are falling behind viral methods with regard to outcomes might still be a matter of “delivery”, including passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release. Behavior in the physiological environment is the most important hurdle for vectors (e.g. p. 13, left column, 4th full paragraph). Thus, viral vector delivery of nucleic acid still suffer from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems. Nonviral delivery of nucleic acid still face the hurdle of passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release.
Lenzi et al. (2014, NCBI Bookshelf, A Service of the National Library of Medicine, National Institute of Health, Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington (DC): National Academies Press (US), pages 1-16) discuss scientific hurdles of gene transfer in vivo. Some scientific hurdles, such as the absence of efficient delivery systems, difficulty with sustained expression, insertional mutagenesis and host immune reactions, remain formidable challenges to the field of gene transfer. Many of the hurdles have to do with providing efficient gene delivery. For examples, the vector uptake and distribution must be tightly controlled so that expression of the vector-encoded gene remains within the therapeutic range-if the expression is too low, the functional protein product may not be produced at a high enough concentration to effectively restore the intended biochemical pathway. Transcription of the new genetic material must remain stable so that the transgene is expressed as long as necessary to treat the disease. The degree to which the vector containing the transgene is taken up in a sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the efficiency of interactions between vector and host cell receptors. The ideal vector would be cell-type specific, but the design of either non-viral or viral vectors that successfully target a specific cellular receptor has been elusive despite a great deal of effort. To date, re-engineered viral vectors are often too large, too unstable, or otherwise unable to reach the nucleus of some cell types. Non-viral gene delivery remains prohibitively inefficient for most therapeutic applications (e.g. p. 10, under “Scientific Hurdles”). For viral vectors, especially adenoviral and adeno-associated viral vectors, the exposed individuals have circulating antibodies that can interfere with transduction of closely related recombinant vectors. The control of an unanticipated immune response can be complicated by the challenge of "turning off" expression of transgene driven by constitutive, non-conditioned promoter sequence specifically designed to always be "on" (e.g. p. 11, 1st paragraph).
In addition, post-dated art Bulcha et al. (2021, Signal Transduction and Targeted Therapy, 6:53, p. 1-24) discusses “Viral vector platforms within the gene therapy landscape” (e.g. Title). Bulcha reports the challenges of rAAV vector for gene therapy include immunogenicity towards the vector remains the largest challenge for AAV-based gene therapies. In fact, the immune system will always be a major barrier for any gene therapy approach. The adaptive immunity to the capsid and the foreign transgene represents major factors for decreased efficacies (e.g. p. 14, bridging left column and right column). “Mechanisms for innate immunity have been well-described in response to viruses, but exploration of innate immune response towards AAV vectors is understudied… In addition, evidence is accumulating for the possibility that the AAV vector genome can elicit an innate immune response, necessitating an area of research that is critically needed” (e.g. p. 14, right column, 2nd full paragraph). Finally, a challenge that must be confronted is managing the right treatment doses, which may be at the heart of the strong immunological responses and subsequent toxicities seen in recent trials… These studies and others indicate that further evaluation of the appropriate routes of administration, capsid choice, and vector genome designs are still needed, even for approved drugs (e.g. Bridging, p. 14, right column and p. 15, left column).
It is apparent that for systemic administration of vectors, the liver is often the default destination, presenting a barrier when other organs are the intended targets. Endothelial cell layers, especially those within the blood-brain barrier pose a physical barrier for entry into a tissue and there is immune response against vectors. The degree to which the vector containing the nucleic acid sequence is taken up in a sufficient number of target cells is influenced by vector size and stability, extent of target tissue vasculature, and the efficiency of interactions between vectors and host cell receptors. The challenges of AAV vector for gene therapy including immunogenicity towards the vector remains the largest challenge for AAV-based gene therapies. Administration routes play an important role to determine whether sufficient vector can be obtained at target sites in a subject. Different administration routes of the nucleic acid can result in different efficiency of gene expression and can influence whether sufficient expressed gene product can be obtained at the target cells so as to perform its purpose in vivo.
Nanoparticle system and administration routes:
There are various barriers for nanoparticle administration (oral, intravenous, intrathecal, intraperitoneal, topical, intramuscular, subcutaneous, intradermal, inhalation, intravitreal, etc.) to reach the target site in treating neoplastic disorders, which was unpredictable before the effective filing date of the instantly claimed invention. There are various barriers before a nanoparticle can reach its target site, such as layers of dermal cells, blood vessel wall, cell membranes, extracellular matrix between the cells, blood-brain-barrier for reaching cells in the brain, etc. Whether or not a nanoparticle can reach target sites in vivo depends on the administration route, which will determine whether the nanoparticle has the efficiency to reach target sites to exert therapeutic effects to treat neoplastic disorders in a subject. There is no evidence of record that demonstrates administration of nanoparticles containing nucleic acids via various administration routes would be able to provide sufficient nucleic acids to the target site in said subject such that the nanoparticle could provide sufficient therapeutic effects in treating various neoplastic disorders.
Post-dated Wang et al (J Control Release. 12 Oct 2020; 329:894-906) states that although recent studies have demonstrated promising advances with exosome-based drug delivery systems, several challenges severely hinder further development of exosomes for clinical applications (abstract). Exosomes exhibit nonspecific biodistribution into unintended organs, including the liver, spleen, lung, kidneys and pancreas and is a huge challenge for exosome-based drug delivery (p. 903, “Challenges . . . as a drug delivery carrier in vivo”, para 1). Developing exosomes as drug carriers for “non-conventional” therapeutic applications, e.g., transmucosal, conjunctival, ocular, cutaneous, pulmonary, delivery are rarely investigated. Challenges of developing drug delivery systems include understanding how exosomes can 1) penetrate physical barriers such as epithelial tight junctions in different tissues and 2) escape clearance by local tissue fluid and enzyme under physiological conditions (p. 903, “Challenges . . . as a drug delivery carrier in vivo”, para 3).
Post-dated Zheng et al (Bioconjugate Chem., 11 March 2019; 30(4): 994-1005) states that “we still do not understand how exosomes in the brain realize intracellular communication. Second, we still do not know how peripheral exosomes access the brain and deliver their cargoes into the CNS” (p. 1002, Conclusion, para 2). The drug loading approaches, source selection, stability, and targeting properties of exosomes are the major factors that determine the clinical translation value of exosomes as brain drug delivery systems (same para).
Post-dated Zhao et al (Biomed Pharmacother. 26 May 2020;128:110237) states that the technology of exosome production and quality control is flawed, the storage stability of exosome production are not clearly studied, and the specific functions of exosomes are not fully understood yet, so it is difficult to predict the long-term safety and efficacy of exosomes (p. 7, para 3).
It appears that 1) there are various barriers before a cell can reach its target site, 2) nonspecific biodistribution into unintended organs, including the liver, spleen, lung, kidneys and pancreas and is a huge challenge for exosome-based drug delivery, 3) fast elimination of nucleic acid nanoformulations from circulation and off-target delivery of nucleic acids, 4) PEG impairs cellular uptake and may reduce endosomal escape efficacy, 5) efficacy of lipid nanoparticles endosomal escape and cellular uptake are not very high and require additional optimization, and 6) drug loading approaches, source selection, stability, and targeting properties of exosomes are the major factors that determine the clinical translation value of exosomes as brain drug delivery systems.
The extremely broad scope of the claims and lack of guidance in the specification exacerbates a highly unpredictable art regarding using gene/immunotherapy to treat/prevent/inhibit/ameliorate all neoplastic disorders. While the results presented in the art do not necessarily preclude Applicant’s hypothesis, they certainly fail to support it in its totality that any splicing modulating agent can treat/prevent/inhibit any and all neoplastic disorder on its own. Applicants do not provide the details of how the “splicing modulating agent” as broadly claimed could be used to treat subjects with malignant neoplasms nor is there a reduction to practice the instant method of treating/preventing/inhibiting any and all neoplastic disorders with the generally claimed “splicing modulating agent” and there is only reduction to practice of ameliorating melanoma and breast cancer. Consequently, the prior and post-filling art, when combined with the lack of disclosed direct experimental test of Applicant’s hypothesis, shows that one of ordinary skill would have no basis to reasonably predict or conclude that the “splicing modulating agent” could be used alone in the claimed method of treating/preventing/inhibiting/delaying the onset of any and all malignant neoplastic disorders in a subject via various administration routes. It is noted that, though not controlling, the lack of working examples is a factor to be considered in a case involving both physiological activity and an underdeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, they run the risk that unless one of skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them (Ex parte Sudilosky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971)).
In essence, the specification merely presents an idea of, and leaves it entirely up to the
practitioner to determine whether the method would produce a therapeutically relevant effect in a subject having any malignant neoplastic disorder other than melanoma or breast cancer, and if so, how to carry out the claimed method. It has been established by legal decision that a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion. Tossing out the germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor or exemplified in the specification, reasonable detail must be provided in order to enable one of ordinary skill to understand and carry out the invention. It is true that a specification need not disclose what is well known in the art. However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph.
Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would not know how to practice the claimed invention and would require undue experimentation to practice over the full scope of the invention claimed.
The amount of experimentation necessary:
The specification only describes ameliorating melanoma with an sgRNA that targets 3’ or 5’ splice sites of exon 4 of tyrosinase gene via intramuscular injection in an immunocompetent subject and ameliorating breast cancer in an immunocompetent subject via intramuscular immunization with an sgRNA that targets 3’ splice site of exon 6 of heterogeneous nuclear ribonucleoprotein A/B. One of ordinary skill in the art could not reasonably take these working examples and readily or immediately apply these splicing modulating agents in the claimed method to treat or prevent neoplastic disorders in any subject using any administration route as broadly embraced by the claims. These teachings do not reasonably support these splicing modulating agents as a potential preventative for any neoplastic disorder and does not support these splicing modulating agents as a potential treatment (i.e., able to ameliorate symptoms only) other than melanoma or breast cancer. One of ordinary skill in the art before the effective filing date of the claimed invention would be required to trial and error identify and select a “subject” from a broad genus of potential disease populations, as well as from subpopulations of disease progression for treatment, preparation of various vectors/matrices/vehicles/nanoparticles/microparticles for the expression of various nucleic acids (“splicing modulating agent”), administration of the various vectors/matrices/vehicles/nanoparticles/microparticles to various subjects via various administration routes, trial and error experimentation to determine whether sufficient agents reach the target sites in vivo, trial and error experimentation to determine whether sufficient “splicing modulating agent” is expressed at the target site in vivo, and trial and error experimentation to determine whether therapeutic effect can be provided to ameliorate various pathological symptoms of various malignant neoplasms in vivo.
For the reasons set forth above, one skilled in the art before the effective filing date of the claimed invention would not be able to make and/or use the invention as claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of the art. Therefore, claims 31, 33-34, 37, 39, 42, and 66 are rejected under 35 U.S.C. 112(a) for failure to meet the enablement requirement.
Response to Arguments
Applicant’s arguments regarding the 112(a) scope of enablement rejection has been fully considered but are not persuasive. Due to limited time available to respond to Applicant’s arguments, these responses have been condensed.
On p. 14-34 of Remarks, Applicant argues, in sum, that the specification enables the claimed methods across the full range of splicing modulation agents encompassed by the claims, but that the amendment to independent claim 31 now defines two classes of splicing modulation agents only. Applicant argues that the disclosure is enabled for the full breadth of neoplastic disorders and points to examples 1-2, 4-5, and 10-12 which relate to identification of target genes overexpressed in tumors, showing neoantigens are immunogenic in animal models across B16-F1 (melanoma) and 4T1 (metastatic murine breast cancer) cell lines. Applicant argues that the claimed method does not recite the use of a single treatment modality and that, rather, one of ordinary skill would understand that the target of the agent will vary according to the protein that is overexpressed in the target neoplastic disorder. Applicant provides newly filed Declaration of Dr. Rotem Karni (herein “Karni Declaration”) to support these contentions.
In response, the examiner disagrees. The examiner’s position regarding the enablement rejection remains unchanged. The claims embrace the prevention of malignant neoplastic disorders and the treatment of any malignant neoplastic disorders with a vast genus of “splicing modulating agents”. The specification is devoid of any concrete data that can be extrapolated to the prevention of any malignant neoplasms in its entirety and only has sufficient data to enable the amelioration of symptoms associated with melanoma (via intramuscular immunization of an sgRNA wherein said sgRNA targets 3’ or 5’ splice sites of exon 4 of tyrosinase gene) and breast cancer (intramuscular immunization an sgRNA wherein said sgRNA targets 3’ splice site of exon 6 of heterogeneous nuclear ribonucleoprotein A/B). Applicant is essentially seeking to monopolize entire classes by their function even though these classes are much broader than the exemplary splicing modulating agents disclosed. With regards to prevention, the examiner notes that the instant specification does not provide any working examples a method of preventing nor does it provide adequate guidance on how to overcome the art-recognized difficult nature of this goal. One skilled in the art could not practice the method to achieve the results of prevention of a malignant neoplastic disorder as claimed. This is because the specification lacks the critical steps necessary in presenting some type of predictable response in populations or subpopulations of subjects deemed necessary to prevent any neoplastic disorder, benign or otherwise. Reasonable guidance with respect to preventing and treating all malignant neoplastic disorder relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to a malignant neoplastic disorder or have had a malignant neoplastic disorder. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of the onset of a neoplastic disorder and link those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Such is not provided in the instant specification. While the Karni Declaration is appreciated and has been considered, the Declaration is directed to hnRNPAB targeting in 4T1 mammary cancer cells (as the examiner pointed out is enabled by the specification) and Tma7 exon skipping in B16 melanoma model (again, the examiner pointed out above that the specification is enabled for this as well). The Declaration does not, however, address the applicability of hnRNPAB or Tma7 exon targeting (via the same or similar “splicing modulating agents) in malignant neoplasms Applicant is attempting to argue is within the scope of the claims. Applicant has not shown that the broad genus of “splicing modulating agents” embraced by the claim can be administered to treat all malignant neoplasm as broadly embraced by the claims. Applicant cannot attempt to take possession of entire genus/class of “splicing modulating agents” to treat all malignant neoplastic disorders (e.g., a single “splicing modulating agent” being able to treat entire classes of malignant cancers). Thus, the rejection is proper and has been maintained.
Written Description
Claims 31, 33-34, 37, 39, 42 and 66 remain 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 have been amended and claim 66 is newly added; the rejection is recast and modified, however, most of the substantive points remain unchanged as posited in the Non-Final Office action mailed 8/21/2025.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
Claims 31, 33-34, 37, 39, 42 and 66 are directed to a method for treating, inhibiting, or ameliorating at least one neoplastic disorder in a subject, wherein said neoplastic disorder is a malignant neoplastic disorder, the method comprising the step of: administering to said subject at least one splicing modulating agent comprising at least one nucleic acid sequence, or of any vector, vehicle, matrix, nano- or micro-particle or composition comprising said at least one agent, wherein said at least one nucleic acid sequence of said agent targets at least one target nucleic acid sequence that participates directly or indirectly in at least one splicing event of a target gene; wherein introduction of said agent into said target cell in said subject induces at least one aberrant splicing event via said target nucleic acid sequence; and wherein said aberrant splicing event results in the production of at least one neoantigen expressed by said target cell, thereby activating an immune response directed against said target cell in said subject; wherein said splicing modulating agent comprises at least one of: (a) at least one oligonucleotide comprising a nucleic acid sequence complementary to at least part of said target nucleic acid sequence; and (b) at least one nucleic acid sequence comprising at least one guide RNA that targets at least one protospacer within said target nucleic acid sequence, or any nucleic acid sequence encoding said gRNA, said gRNA guides at least one programmable engineered nuclease (PEN) to said target nucleic acid sequence in said target gene; and wherein said at least one target nucleic acid sequence that participates directly or indirectly in at least one splicing event is comprised within at least one coding transcript characterized by at least one of: (i) said coding transcript comprises at least three exons; (ii) at least one of said exons is of a length not divisible by three; and (iii) the coding transcript comprises at least one intron.
The claims read on using nucleic acid sequence (any sequence, including sense and antisense oligonucleotides of any length, as well as those contained in any vector, matrix, vehicle, nanoparticle, microparticle, and general compositions containing the nucleic acid sequence) as a “splicing modulating agent” capable of treating/preventing/inhibiting/delaying the onset of malignant neoplasms. Dependent claim 33 also requires the administration of any “peptide derived from a neoantigen or any derivative, enantiomer, fusion protein, conjugate, or polyvalent dendrimer” with the “splicing modulating agent.”
All of the outlined genera above are problematic as the specification fails to teach and/or provide support for the possession of the nucleic acid sequences, vectors, matrices, vehicles, nanoparticles, microparticles, peptides derived from a neoantigen or any derivatives, enantiomers, fusion proteins, conjugates, or polyvalent dendrimers as broadly claimed. In support of the claimed genera of nucleic acid sequences (“splicing modulating agent”) and peptides derived from a neoantigen or any derivative, enantiomer, fusion protein, conjugate, or polyvalent dendrimer, the specification discloses an sgRNA that targets 3’ or 5’ splice sites of exon 4 of tyrosinase gene via intramuscular injection in an immunocompetent subject and ameliorating breast cancer in an immunocompetent subject via intramuscular immunization with an sgRNA that targets 3’ splice site of exon 6 of heterogeneous nuclear ribonucleoprotein A/B as well as the administration of peptides derived from the spliced TYR and hnRNPAB genes (see working examples 2-13). However, there are no other working examples from Applicant’s disclosures in which any other nucleic acid sequences, vectors, matrices, vehicles, nanoparticles, microparticles, peptides derived from a neoantigen or any derivatives, enantiomers, fusion proteins, conjugates, or polyvalent dendrimers, or compositions containing the nucleic acid sequence broadly embraced by the claims were created, screened, or tested. One of ordinary skill in the art would not immediately recognize that the claimed expansive genera of nucleic acid sequences and co-administered peptides would be able to perform the claimed function of treating/preventing/inhibiting/delaying the onset of neoplastic disorders based on the specification alone.
The data generated as described in the specification cannot be reasonably extrapolated and applied to support possession of the entire claimed genus of splicing modulating agents or co-administered peptides, because no one species, combination, or variant accounts for the variability amongst the claimed genus. As in Ariad, merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species. “A patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” Brenner v. Manson, 383 U.S. 519, 536 (1966).
The specification, then, is considered devoid of sufficiently detailed, relevant, identifying characteristics demonstrating that Applicant was in possession of the claimed genus of splicing modulating agents, variants, or fragments, i.e., additional complete or partial structures, other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure, or some combination thereof demonstrating possession of the claimed genus. Therefore, claims 31, 33-34, 37, 39, 42 and 66 are rejected under 35 U.S.C. 112(a) for lack of written description.
Response to Arguments
Applicant’s arguments and newly filed Declaration of Dr. Rotem Karni (herein “Karni Declaration”) have been fully considered but are not persuasive.
On p. 34-40 of Remarks, Applicant argues, in sum, that the instant specification explicitly discloses the functional and structural characteristics of splicing modulating agents in p. 13-17 and the aberrant spicing event resulting in the production of neoantigen is described on p. 12. Applicant further argues that the specification details the structures and mechanisms of action for multiple classes of splicing modulating agents, specifically antisense oligonucleotides, on p. 19-25. For the example of TYR, 20 different ASOs were screened for induction of exon 4 skipping with two potent ASOs identified (Fig. 3A). This, along with disclosures on p. 26-31, Applicant argues, supports the multiple classes of splicing modulating agents to generate neoantigens. Applicant further argues that the specification extensively describes viral and non-viral vectors suitable for delivery of SMAs (p. 31-32 of specification), formulations to incorporate these agents into nanoparticles and microparticles (p.88-89), generalized guidance on identifying additional target genes involved in cancer (p. 109-111; Table 1-2), and various administration methods for the agents (p. 32; p. 86-88). Applicant provides newly filed Karni Declaration to support these contentions.
In response, the examiner disagrees. Applicant’s instant specification does not provide adequate support for the entire genus of splicing modulating agents capable of treating/preventing/inhibiting/ameliorating all malignant neoplasms. As previously discussed, written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) (“[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention.”) (see MPEP (II)(3)(a)(ii)).
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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of 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) (see MPEP (II)(3)(a)(ii)). Thus, satisfactory disclosure of a "representative number" depends on whether one of ordinary skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed.
The question at issue, then, is whether one of ordinary skill in the art could predict the operability of any species of splicing modulating agents other than the two species disclosed in the instant specification’s working examples such that they would recognize that Applicant was in possession of the necessary common attributes or features possessed by the members of the genus. Put more simply, would one of ordinary skill recognize Applicant to be in possession of all potential splicing modulating agents as broadly claimed that can be used to treat benign and malignant neoplasms in immunocompetent and immunodeficient subjects. The claimed invention, which essentially claims all potential splicing modulating agents, cannot be adequately supported by an instant specification that describes only a two types of agents (sgRNA against TYR gene and sgRNA against HNRNABP) that meets the instantly claimed features of ameliorating melanoma and breast cancer, respectively (see MPEP (II)(3)(a)(ii); see AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) which held that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies). Thus, the rejection is proper.
New Matter – Necessitated by Amendments
Claims 31, 33-34, 37, 39, 42 and 66 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.
MPEP 2163 provides a procedure for evaluating the adequacy of written description to support the claim elements: a) determining what the claim covers as a whole, b) reviewing the entire application to understand how applicant provides support for the claimed invention including each element and/or step, and 3) determining whether there is sufficient written description to inform a skilled artisan that inventor was in possession of the claimed invention as a whole at the time the application was filed. The proscription against the introduction of new matter in a patent application serves to prevent an applicant from adding information that goes beyond the subject matter originally filed. See In re Rasmussen, 650 F.2d 1212, 1214, 211 USPQ 3232, 326 (CCPA 1981).
Mere rephrasing of a passage does not constitute new matter. Accordingly, a rewording of a passage where the same meaning remains intact is permissible. In re Anderson, 471 F.2d 1237, 176 USPQ 331 (CCPA 1973) (see MPEP 2163.07(I)). The mere inclusion of dictionary or art recognized definitions known at the time of filing an application may not be considered new matter. The subject matter of the claim need not be described literally (i.e., using the same terms or in haec verba) in order for the disclosure to satisfy the description requirement. However, if a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, conclusion that the claimed subject matter is not described in that application is appropriate, resulting in the rejection of the claims affected under 35 U.S.C. 112(a).
However, in the instant case, Applicant has amended the definition for “treatment” and “inhibit”. Treatment, originally defined as “ameliorating one or more clinical indicia of disease activity by administering a pharmaceutical composition of the invention in a patient having a pathological disorder and administering of a therapeutic amount of the composition which is effective to ameliorate undesired symptoms associated with a disease, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, or to improve survival rate or more rapid recovery, or a combination of two or more of the above,” was amended to remove, inter alia, “to prevent the manifestation of such symptoms before they occur”. “Inhibit”, originally defined as “the restriction or prohibition of the progress and exacerbation of pathologic symptoms or a pathologic process progress”, was amended to remove the recitation of “or prohibition”. In this regard, the newly filed amendments materially change the scope of “treatment” and “inhibition” as recited in the instant claims, constituting new matter.
Accordingly, the amendments to the instant specification to remove definitions constitute new matter to the scope of the instant claims. Claims 33-34, 37, 39, 42 and 66 are included in this rejection as they depend on claim 31.
Claim Interpretation
Claims 31, 34, 37, and 39 all recite in line 1 “at least one of . . .” The examiner is interpreting in that satisfying either (a) or (b)/(I) or (II) or (III) is sufficient to meet the respective claim limitations.
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.
Claim(s) 31, 33-34, 39, and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al (Nucleic Acids Res. 18 Aug 2010; 38(22):8348-56) in view of Jayasinghe et al (Cell Rep. 2018 Apr 3;23(1):270-281; Ref. 9 of Non-patent literature in IDS filed 18 Feb 2022; previously cited).
Bauman teaches the anti-tumor activity of splice-switching oligonucleotides (title). The reference teaches splice-switching oligonucleotides (SSOs) modulate alternative splicing by hybridizing to pre-mRNA sequences involved in splicing and blocking access by various splicing factors (Introduction, para 1) (“wherein said splicing modulating agent comprises at least one of: (a) at least one oligonucleotide comprising a nucleic acid sequence complementary to at least part of said target nucleic acid sequence” as in instant claim 32). Through alternative splicing, the Bcl-x gene yields two major protein isoforms with opposing functions, anti-apoptotic Bcl-xL (which confers resistance to chemotherapeutic drugs) and pro-apoptotic Bcl-xS (Introduction para 2; Fig. 1A). Redirection of Bcl-x splicing from Bcl-xL to -xS induced apoptosis and increased chemosensitivity in cancer cells in culture (same para). Use of the downstream or upstream alternative 5′-splice site within exon II of Bcl-x pre-mRNA yields anti-apoptotic Bcl-xL or pro-apoptotic Bcl-xS, respectively (Fig. 1 A) (i.e., BCL-XL contains 4 exons and BCL-XS has 3 exons; “wherein said at least one target nucleic acid sequence that participates directly or indirectly in at least one splicing event is comprised within at least one coding transcript characterized by at least one of: (i) said coding transcript comprise at least three exons” as in instant claim 31 in-part; “(II) said target nucleic acid sequence is comprised within an exon . . . wherein said exon is not the first or last exon in said transcript” as in instant claim 34). SSO targeted to the downstream splice site redirects the splicing machinery to the upstream alternative splice site, resulting in a simultaneous decrease in production of Bcl-xL and increase in production of Bcl-xS (Fig. 1A) (“wherein said splicing modulating agent comprises at least one of: (a) at least one oligonucleotide comprising a nucleic acid sequence complementary to at least part of said target nucleic acid sequence” as in instant claim 31 in-part; “wherein at least one of: (I) said at least one target nucleic acid sequence that participates directly or indirectly in at least one splicing event comprises at least one of . . . an exonic splicing enhancer” as in instant claim 34). Transfection of B16F10 cells (melanoma cells) with MOE-PS Bcl-x SSO targeted to the downstream 5′-splice site of Bcl-x exon 2 (Figure 1) induced a dose-dependent shift in splicing of Bcl-x pre-mRNA from anti-apoptotic Bcl-xL to pro-apoptotic Bcl-xS, while a control SSO had no effect on splicing (Results, para 1; Figure 2A and B) (“wherein said neoplastic disorder is selected from the group consisting of . . . a melanoma” as in instant claim 66). To facilitate SSO delivery to cancer cells in tumor-bearing mice, an LPD NP was used (“Activity of Bcl-x SSO in vivo”, para 1). In the absence of treatment, the mice die ∼22 days following inoculation (“Activity of Bcl-x SSO in vivo”, para 2). RT–PCR analysis of total RNA from the tumor-bearing lungs of animals euthanized on Day 7 showed induction of Bcl-xS mRNA expression in animals treated with the Bcl-x SSO NP formulation (same para). This effect was dose-dependent, as increasing the number of injections resulted in a greater degree of Bcl-x splice-switching from Bcl-xL to Bcl-xS mRNA in the tumor nodules (same para) (“wherein at least one of: (a) said neoplastic disorder is cancer and wherein said target cell is a cancerous cell” as in instant claim 39). The reference concluded that the data indicate that SSO-induced redirection of Bcl-x pre-mRNA splicing from Bcl-xL to -xS induced apoptosis and subsequent cell death in a dose-dependent manner in B16F10 melanoma cells in culture (Figures 2 and 3). In vivo, redirection of Bcl-x pre-mRNA splicing was associated with a significant reduction of tumor burden in rapidly growing and highly tumorigenic B16F10 lung metastases (Figure 5A–C) (“a method for treating, inhibiting, or ameliorating at least one neoplastic disorder in a subject, the method comprising the step of: administering to said subject at least one splicing modulating agent comprising at least one nucleic acid sequence or of any . . . nanoparticle . . . . comprising at least one agent, wherein said at least one nucleic acid sequence of said agent targets at least one target nucleic acid sequence that participates directly or indirectly in at least one splicing event of a target gene; wherein introduction of said agent into said target cell in said subject induces at least one aberrant splicing event via said target nucleic acid sequence via said target nucleic acid sequence” as in instant claim 31 in-part). Modification of Bcl-x pre-mRNA splicing alone induced cell death, whereas in non-small cell lung carcinoma (A549) cells adjuvant chemotherapy was needed (Discussion, para 2) (“wherein at least one of: (b) said subject is further treated with at least one immunomodulatory agent” as in instant claim 33).
The difference between Bauman and the invention as instantly claimed is that it does not teach that the aberrant splicing event results in the production of at least one neoantigen expressed by the target cell, and activates an immune response directed against the target cell (instant claim 31 in-part).
Jayasinghe teaches that splice-site-creating mutations induce neoantigen production that is several folds more immunogenic than missense mutations (abstract). Specifically, the reference teaches that alternative splice forms for some important genes related to tumorigenesis are highly immunogenic and can contain 40 or more unique neoantigens (“Neoantigens introduced by SCMs” para 1). To test whether SCMs affect immune response, researchers compared the expression of T cell markers PD-1, CD8A and CD8B and PD1 immune checkpoint blockades PD-L1 and PD-L2 (Figure 7). They selected six cancer types (BRCA, BLCA, HNSC, LUAD, LUSC, and SKCM) with sufficient samples containing SCMs for adequate statistical power. Both T cell markers (PD-1, CD8A, and CD8B) and immune checkpoint blockade PD-L1 show increased expression in samples with SCMs compared to samples without SCMs (Figure 7), indicating alternative splice forms induced by SCMs increase the overall immunogenicity of these cancers. The reference concludes that alternative splice forms induced by SCMs are highly immunogenic and correlated with a high T cell immune response and an elevated PD-L1 expression, suggesting the potential for immunotherapy in these samples (“Discussion”, last para) (“aberrant splicing event results in the production of at least one neoantigen expressed by said target cell, thereby activating
an immune response directed against said target cell in said subject” as in instant claim 31 in-part).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to treat cancer with an oligonucleotide that induces splicing as taught by Bauman, where the splicing produces a neoantigen and activate the immune system as taught by Jayasinghe, to arrive at the instantly claimed invention. As Jayasinghe shows splice-site-creating mutations induces neoantigen production, one of ordinary skill would have reasonably expected that the oligonucleotide of Bauman to also induce neoantigen production and advantageously increase the overall immunogenicity of the cancer cell and induce high T cell immune response as taught by the prior art.
Response to Arguments
Applicant’s arguments have been fully considered but are not persuasive.
On p. 40-47, Applicant argues, in sum, that the cited references purportedly fail to teach or suggest the claimed immune-mediated neoantigen mechanism or provide a reasoned motivation to combine the Bauman and Jayasinghe references. Applicant argues that the Bauman reference relates to splice-switching oligonucleotides that modulate naturally occurring splicing isoforms while the instant invention is related to non-natural/engineered splice variant. Applicant argues that the mechanism of Bauman to treat tumors is different from that instantly claimed (i.e., directing/mounting an immune response). Applicant further argues that one of ordinary skill would not modify Bauman to the teachings of Jayasinghe to create neoantigens. Applicant argues that even if one of ordinary skill would combine Bauman and Jayasinghe, Bauman is directed to naturally occurring splicing isoforms while the instant claims are related to non-natural splicing variants. Since Jayasinghe describes naturally occurring mutations, the synthetic splicing isoforms claimed cannot be derived from the combination of Bauman and Jayasinghe.
In response, the examiner disagrees. First, the claims embrace both naturally and non-naturally occurring splice modulation. As detailed above, the combination of Bauman and Jayasinghe describe splicing modulating that can be used to treat melanoma and that splice-site creating mutations induce neoantigen production. As stated in the previously mailed Non-Final Office action, the production of the neoantigen is a result of the active method step of administration. Previously cited reference Jayasinghe shows that splicing modulation creates neoantigens and subsequently mounts and immune response against the tumors. One of ordinary skill would then recognize that in performing Applicant’s instant method, neoantigens would be produced and result in an immune response based on the teachings of Jayasinghe. Thus, Applicant’s argument is not persuasive.
Claim(s) 37 and 42 remain rejected under 35 U.S.C. 103 as being unpatentable over Bauman et al (Nucleic Acids Res. 18 Aug 2010; 38(22):8348-56) in view of Jayasinghe et al (Cell Rep. 2018 Apr 3;23(1):270-281; Ref. 9 of Non-patent literature in IDS filed 18 Feb 2022; previously cited) as applied to claims 31-34 and 39 above, and further in view of Karni (US20130089563 A1, 6/16/2011; Published 4/11/2013).
The teachings of Bauman and Jayasinghe in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 31 of which claim 37 and 42 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the splicing modulating agent is an antisense oligonucleotide comprising at least 15 contiguous nucleotide bases complementary to at least part of the nucleic acid sequence that participates directly or indirectly in one splicing event (claim 37) or that the target gene is HNRNPAB and said cancer is breast cancer (claim 42).
Karni teaches a method of diagnosing and treating a glioma or breast cancer (abstract). The reference teaches administering to the subject a therapeutically effective amount of an agent which down-regulates an amount or activity of hnRNP A2/B1 or a target thereof, thereby treating the glioma or metastasized breast cancer (see claim 9 of Karni) (“wherein said target gene is HNRNPAB and said cancer is breast cancer” as in instant claim 42). The reference teaches that the agent is a polynucleotide agent such as an siRNA (see claim 11 and 13 of Karni). Short interfering RNAs derived from dicer activity are typically about 21 to about 23 nucleotides in length (para 172). Downregulation of HNRNP A2/B1 can also be effected by using an antisense polynucleotide capable of specifically hybridizing with an mRNA transcript encoding HNRNP A2/B1 (para 192) (“splicing modulating agent is at least one oligonucleotide, said oligonucleotide is an antisense oligonucleotide comprising at least 15 contiguous nucleotide bases complementary to at least part of the nucleic acid sequence that participates directly or indirectly in one splicing event” as in instant claim 37). The reference teaches that hnRNP A2/B1 is both a marker for the metastatic stage of breast cancer and for patient prognosis and tumor stage and is a putative oncogene in breast cancer (para 95). Several splicing targets of hnRNP A2/B1 change their isoform distribution upon knockdown or overexpression of hnRNP A2/B1 and suggest that hnRNP A2/B1 levels controls the splicing program of a large set of target genes which enhance invasiveness and other metastatic properties of breast cells (same para). Accordingly, the splicing signature of hnRNP A2/B1 targets and/or hnRNP A2/B1 levels may serve as an accurate indication for metastasis of breast tumors and prognosis (same para).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to treat cancer with an oligonucleotide that induces splicing as taught by Bauman and Jayasinghe in combination, where the splicing modulating agent comprises an antisense oligonucleotide that targets HNRNPAB as taught by Karni, to arrive at the instantly claimed invention. As Karni shows antisense oligonucleotides can be used to target HNRNPAB, one of ordinary skill would have been motivated to simply substitute one known element [splicing modulating agent of Bauman and Jayasinghe in combination] for another [splicing modulating agent of Karni] to obtain the predictable result of controls the splicing program of a large set of target genes which enhance invasiveness and other metastatic properties of breast cells as taught by the prior art.
Response to Arguments
Applicant argues on p. 47-50 that Karni does not remedy deficiencies of Bauman and Jayasinghe because targeting HNRNPAB to downregulate expression teaches away from the present invention. Applicant argues that downregulated neoantigen would undermine immunogenic presentation.
In response, the examiner disagrees. Karni was cited to render prima facie obvious using “antisense oligonucleotide” as a splicing modulating agent (as in instant claim 37) and “target gene is heterogeneous nuclear ribonucleoprotein A/B (HNRNPAB), and said cancer is breast cancer” (as in instant claim 42). As detailed above, the Karni reference provides sufficient teaching, suggestion, and motivation to target HNRNPAB using siRNA because, inter alia, “Several splicing targets of hnRNP A2/B1 change their isoform distribution upon knockdown or overexpression of hnRNP A2/B1 and suggest that hnRNP A2/B1 levels controls the splicing program of a large set of target genes which enhance invasiveness and other metastatic properties of breast cells.” In sum, targeting hnRNP A2/B1 with splicing modulation would have downstream effects of reducing levels of the protein, reduce invasiveness, and other metastatic properties of breast cancer cells. Thus, Applicant’s argument is not persuasive.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Lutz et al (WO 2010083338 A2, filed 1/14/2010; published 7/22/2010), which describes a method of treating a subject afflicted with a cancer, said method comprising administering a splice modulating oligonucleotide (SMO) to said subject, wherein an effective amount of said SMO contacts a cell so that said SMO specifically binds to a complementary sequence on a pre-mRNA in at least one of the group consisting of an intron-exon splice site, an exonic splice enhancer (ESE) site, and an intronic splice enhancer (ISE) site, wherein when said SMO specifically binds to said complementary sequence, the exon adjacent to the intron-exon boundary is excluded from the resulting mRNA, wherein said exon is exon 3 of said mRNA encoding HER3, and wherein said SMO increases expression of a HER3Δ3 in said subject and treats said subject afflicted with cancer; the cancer treated includes breast cancer.
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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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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