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 .
The preliminary amendment filed 12/26/24 is acknowledged. Claims 3, 6, 8- 14, and 16 have been amended. Claims 1-16 are pending and under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The use of the term nSolver™ and ProcartaPlex™, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
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 1-16 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 drawn to method for treating a cancer in a subject, wherein the cancer expresses and/or secrets apolipoprotein E (apoE), the method comprising inhibiting expression or activity of apoE, thereby treating the cancer in the subject.
The specification teaches inhibiting expression of apoE comprises decreasing mRNA or protein level of apoE. The specification teaches that the inhibitor of ApoE is a nucleic acid, a regulatory RNA (e.g., siRNA, antisense oligonucleotide, or mRNA), or a small molecule inhibitor. The specification teaches that in some embodiments, the protein that inhibits activity of apoE is an anti-apoE or apoE receptor antagonist, a neutralizing antibody or an antigen-binding fragment thereof. The specification teaches that the agent is an antibody or antigen-binding fragment thereof, such as a monoclonal antibody, human-mouse chimeric antibodies, humanized antibodies, human antibodies, CDR-grafted antibodies, or resurfaced antibodies.
The specification teaches that serum levels of apoE in tumor-bearing apoE-/- mice inoculated with B16 (F10) melanoma cells increased progressively and considerably with tumor growth. The specification teaches that apoE-/- B16 cells lines were generated with CRISPR-Cas9 deletion. The specification teaches that apoE expression was diminished in the apoE-/- clones. The specification teaches that IFNγ production and T cell viability were significantly suppressed when T cells cultured in WT B16 CM as compared to RPMI media control. The specification teaches that apoE-/- conditioned media was similar to RPMI control media alone and did not inhibit T cell activity nor viability. The specification teaches that cell cycle distribution showed that WT conditioned media arrested activated T cells in the G0/G1 phase while apoE-/- conditioned media maintained T cells in the S phase and G2M phase of the cell cycle, similar to control media without prior exposure to tumor cells. The specification teaches that these results indicate that conditioned media derived from B16 tumor cells induces arrest pf stimulated T cells in the G0/G1 phase of the cell cycle, resulting in apoptosis and suppression of cytokine production. The specification teaches that in contrast, the singular absence of apoE in conditioned media rescues the activated T cell phenotype when stimulated with CD3/CD28 beads. The specification teaches that ten out of 27 detectable cytokines suppressed by WT conditioned media returned to baseline levels or were upregulated when T cells were cultured in apoE-/- CM. The specification teaches that COG133, a fragment of apoE peptide which competes with the apoE holoprotein for binding the low-density lipoprotein (LDL) receptors and acts as an apoE mimetic, was tested to determine its effect on T cell activation. The specification teaches that T cell viability was diminished in a dose dependent manner in T cells treated with CD3/CD28 dynabeads and COG133. The specification teaches that apoE secreted from B16 melanoma tumor cells in culture also impair activation of pro-inflammatory dendritic cells. The specification teaches that B16 WT conditioned media suppressed DC activation as determined by cytokine production, but this effect was absent in media from apoE-/- B16-F10 cells. The specification teaches that secretion of IL-10 is diminished when DC were cultured in apoE-/- CM compared to WT CM. The specification teaches that proinflammatory cytokines IL1α, IL1β, RANTES, MIP1α, and IL-28 are all increased with apoE-/- CM compared to WT CM. The specification teaches that COG133 induced secretion of IL-10 from activated DC and suppressed IL-1α, IL-1β, and IL-23 in a dose dependent manner. The specification teaches that COG133 inhibits cytokine secretion induced by immunogenic tumor cells, while anti-apoE blocking antibody enhances cytokines secretion in tumor cell/splenocyte reactions. The specification teaches that exposure of Myc-inhibited immunogenic B16 cells to COG133 repressed IFNγ production, while anti-apoE enhanced IFNγ production. The specification teaches that COG133 suppressed IFNγ production in vaccinated splenocytes co-cultured with Myc inhibited B16 tumor cells. The specification teaches that 14 out of 23 cytokines were significantly upregulated when splenocytes were co-cultured with Myc-inhibited B16 tumor cells; four of them including IFNγ, IL-6, IL-8, and RANTES were suppressed after exposure to COG133. The specification teaches that the apoE receptors lrp8 and ldlr are dominantly expressed on activated T cells and dendritic cells and blocking lrp8 enhanced T-cell activation. The specification teaches that IFNγ production from splenocytes was inhibited by COG133 in WT mice, however, the inhibitory effect was lacking in splenocytes from lrp8-/- mice. The specification teaches that T-cell function is at least partially inhibited by apoE through the lrp8 receptor pathway. The specification teaches that targeting apoE suppressed tumor growth with enhanced mouse survival in a murine melanoma model. The specification teaches that complete deletion of apoE in tumor cells and in the host cell was most effective for inhibition tumor growth, while apoE-/- B16 cells injected into WT mice or WT B16 cells injected into apoE-/- or lrp8 -/- mice partially suppressed tumor growth compared to control.
Although the claims are inclusive of specifically disclosed inhibitors of ApoE expression or activity, the claims are not limited to these specific agents and instead broadly encompass any agent that has the recited function. The claims state that the agent that inhibits ApoE expression or activity comprises an RNAi, siRNA, miRNA, antisense oligo- or polynucleotide, a guide RNA, a polynucleotide coding sequence thereof on a vector, a peptide, a protein or small molecule that binds to apoE or a receptor of apoE, or an anti-apoE or apoE receptor antagonist/neutralizing antibody or antigen-binding fragment thereto. This indicates hundreds, if not thousands, of possible molecules encompassed by the claims. The claims require that the agent exhibit specific functions (i.e., inhibit apoE activity or expression and treat a cancer), but the specification provides no guidance regarding which protein, small molecules, nucleic acids, or other molecules are capable of the required function. Therefore, the specification does not provide adequate written description to identify the broad and variable genus of agents because, inter alia, the specification does not disclose a correlation between the necessary structure of the agents and the function(s) recited in the claims; and thus, the specification does not distinguish the claimed genus from others, except by function.
Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed agent may generically describe the agent’s function, it does not describe the agent itself. A definition by function does not suffice to define the genus because it is only an indication of what the agent does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of agents is highly
variable (i.e., each inhibitor of apoE expression or activity would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed agonists have no correlation between their structure and function.
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the fully described inhibitors of apoE expression or activity (e.g., COG133), and the claimed function(s), this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed inhibitors of apoE expression or activity and encompass a vast genus of agents of varying biological genera. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Given the vast number of agents that are encompassed by the claims, the disclosure of a few species is not sufficiently representative of the broad genus of agonists encompassed by the claims. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed agents, 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 for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601,1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2dl961,1966 (1997); In re Gosteli, 872 F.2dl008,1012,10 USPQ2dl614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
The state of the art regarding the use of inhibitors is ApoE to treat cancer is unpredictable. For instance, Tavazoie et al. (WO 2014/028461 A1, published February 20, 2014) teach treating cancer by increasing the expression level or activity level of Apoe comprising administering a recombinant ApoE peptide (See claim 1). On the contrary, Vitek et al. (WO 2010/002982 A1, published January 7, 2010) teaching using an ApoE peptide inhibitor for treating cancer (See claim 1 and paragraph 0041). Given the discrepancies in the art, it cannot be readily predicted that a particular agent that inhibits expression or activity level of ApoE will treat a particular cancer.
A variety of agents are known in the art and may be identified by their effects. Examples include proteins, antibodies, small molecules, or nucleic acids. The instant claims thereby encompass many genera of chemical and biological molecules, without any described structure that is required for the molecules to perform required functions.
Regarding the encompassed proteins, protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is vey helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in survivin results in the conversion of survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al. and Burgess et al. but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted.
Regarding the encompassed antibodies and antibody fragments, the claims require various functional characteristics of the claimed antibodies and antibody fragments, including the ability to inhibit apoE expression or activity. The functional characteristics of antibodies (including binding specificity and affinity are dictated on their structure. Amino acid sequence and conformation of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. For example, Vajdos et al. (J Mol Biol. 2002 Jul 5;320(2):415-28 at 416) teaches that, “ … Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site." The art shows an unpredictable effect when making single versus multiple changes to any given CDR. For example, Brown et al. (J Immunol. 1996 May; 156(9):3285-91 at 3290 and Tables 1 and 2), describes how the VH CDR2 of a particular antibody was generally tolerant of single amino acid changes, however the antibody lost binding upon introduction of two amino changes in the same region.
The claims encompass an extremely large number of antibodies that have specific required functions. Recently, the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen V. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself even when preparation of such an antibody would be routine and conventional. Amgen, 872 F.3d at 1378-79. A key role played by the written description requirement is to prevent "attempt[s] to preempt the future before it has arrived." Ariad at 1353, (quoting Fiers V. Revel, 984 F.2d at 1171). Upholding a patent drawn to a genus of antibodies that includes members not previously characterized or described could negatively impact the future development of species within the claimed genus of antibodies. In the instant case, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements. Therefore, neither the art nor the specification provide a sufficient representative number of antibodies or a sufficient structure-function correlation to meet the written description requirements.
Regarding small molecule inhibitors of a particular protein target, the prediction of binding to a target, much less the activating activity, is highly unpredictable. According to Guido et al. (Curr Med Chem. 2008; 15(1):37-46), accurately predicting the binding affinity of new drug candidates remains a major challenge in drug discovery (see page 37). There are a vast number of possible compounds that may function as an activator of a toll-like receptor, many of which have likely not been discovered. Relying on virtual screening also lends unpredictability to the art regarding identification of molecules that would be capable of the required functions of the instant claims. Guido et al. teach that there are two main complex issues with predicting activity for a small molecule: accurate structural modeling and/or correct prediction of activity (see page 40). As taught by Clark et al (J. Med. Chem., 2014, 57 (12), pp 5023–5038), developing selective JAK inhibitors is difficult. Even when guided by structure, JAK structure-activity relationships have been challenging owing to the similarities of the enzymes (see page 5028). Therefore, it is impossible for one of skill in the art to predict that any particular encompassed small molecule therapeutic would function to activate a particular protein.
Regarding nucleic acid inhibitors of a particular protein target, the efficacy of any possible RNA interference therapeutic modality is highly unpredictable. This unpredictability stems from an inability to predict the effects of any particular sequence on the expression or function of any target. As taught by Aagaard et al. (Advanced Drug Delivery Reviews 59 (2007) 75-86), the development of RNAi based therapeutics faces several challenges, including the need for controllable or moderate promoter systems and therapeutics that are efficient at low doses (see page 79), the ability of an unpredictable number of sequences to stimulate immune responses, such as type I interferon responses (see page 79), competition with cellular RNAi components (see page 83), the side effect of suppressing off targets (see page 80), and challenging delivery (see page 83). The success of antisense strategies, including anti-RNA and anti-DNA strategies are also highly unpredictable. Warzocha et al. (Leukemia and Lymphoma, Vol. 24. pp. 267-281) teach that the efficacy of antisense effects varies between different targeted sites of RNA molecules and three dimensional RNA structures (see page 269), while DNA- targeting strategies have numerous problems including a restricted number of DNA sequences that can form triple helices at appropriate positions within genes and the inaccessibility of particular sequences due to histones and other proteins (see page 269). These references demonstrate that variation in RNA or DNA based therapeutics will often dramatically affect the biological activity and characteristics of the intended therapeutic. Given the teachings of Aagaard et al. and Warzocha et al., the claimed RNA and DNA therapeutics could not be predicted based on the targets selected or similarities to the disclosed example therapeutics. Therefore, it is impossible for one of skill in the art to predict that any particular encompassed RNA or DNA based therapeutic, such as RNAi molecules and antisense oligonucleotides, would function as a TLR 7 or 8 agonist.
Given the teachings of these references that point out the limitations and pitfalls of using sequence to predict functions, and the lack of representative number of species across the breadth of the genus, one of skill in the art would reasonably that the instant disclosure does not meet the written description provision of 35 U.S.C. 112(a).
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claims 1-16 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 melanoma comprising administering an inhibitor of apoE expression or activity, wherein the inhibitor is COG133, does not reasonably provide enablement for all cancers and all inhibitors of apoE expression or activity. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability, 5) existence of working samples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
1) Nature of the invention and 6) Breadth of the claims
The nature of the invention is a method for treating a cancer in a subject, wherein the cancer expresses and/or secrets apolipoprotein E (apoE), the method comprising inhibiting expression or activity of apoE, thereby treating the cancer in the subject.
Therefore, the nature of the invention is a chemical case, wherein there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; See MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to make and use the claimed inhibitor of apoE expression or activity for treating a cancer, with a reasonable expectation of success, because it would not be predictable from the disclosure of any particular species what other species may or may not work; See MPEP 2164.03.
Although the claims are inclusive of specifically disclosed inhibitors of ApoE expression or activity, the claims are not limited to these specific agents and instead broadly encompass any agent that has the recited function. The claims state that the agent that inhibits ApoE expression or activity comprises an RNAi, siRNA, miRNA, antisense oligo- or polynucleotide, a guide RNA, a polynucleotide coding sequence thereof on a vector, a peptide, a protein or small molecule that binds to apoE or a receptor of apoE, or an anti-apoE or apoE receptor antagonist/neutralizing antibody or antigen-binding fragment thereto. This indicates hundreds, if not thousands, of possible molecules encompassed by the claims. The claims require that the agent exhibit specific functions (i.e., inhibit apoE activity or expression and treat a cancer), but the specification provides no guidance regarding which protein, small molecules, nucleic acids, or other molecules are capable of the required function.
The claims also broadly encompass treating any cancer. The breadth of the claim exacerbates the complex nature of the subject matter to which the present claims are directed. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. For example, there are solid cancers of the brain, spine, live, prostate, testes, ovaries, bile duct, blood vessels, lung and pleural cavity, thyroid, skin (including melanoma), colon, prostate, kidneys, breasts, testicles, vulva and vagina, uterus, cervix, fallopian tubes, thymus, stomach, esophagus, spleen, salivary glands, heart, oral cavity, adrenal glands, eye, head and neck, bladder, bone, and gall bladder. Each of these types of cancer have potentially dozens of sub-categories that each have unique physiological and etiological characteristics.
The claims and specification also establishes the breadth of the claims by teaching that the caner is selected from esophageal carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, cervical squamous cell carcinoma, endometrial adenocarcinoma, bladder cancer, urothelial carcinoma, lung cancer, non-small cell lung cancer, colorectal cancer, rectal cancer, endometrial cancer, skin cancer, head & neck squamous cell carcinoma, brain cancer, glioblastoma multiforme, non-CNS tumor, breast cancer, gastric cancer, gastroesophageal cancer, gastroesophageal adenocarcinoma, pancreatic cancer, prostate cancer, ovarian cancer, melanoma, nasopharyngeal carcinoma, anal carcinoma, mesothelioma, renal cell carcinoma, gallbladder/cholangiocarcinoma, pancreatic carcinoma, penile squamous cell carcinoma, and vulvovaginal carcinoma.
(5) The state of the prior art and (7) The predictability or unpredictability of the art
The state of the art regarding the use of inhibitors is ApoE to treat cancer is unpredictable. For instance, Tavazoie et al. (WO 2014/028461 A1, published February 20, 2014) teach treating cancer by increasing the expression level or activity level of Apoe comprising administering a recombinant ApoE peptide (See claim 1). On the contrary, Vitek et al. (WO2010002982 A1, published January 7, 2010) teach using an ApoE peptide inhibitor for treating cancer (See claim 1 and paragraph 0041). Given the discrepancies in the art, it cannot be readily predicted that a particular agent that inhibits expression or activity level of ApoE will treat a particular cancer.
While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regards to treating all cancers with a single treatment is underdeveloped. In particular, there is no known anticancer agent that is effective in treating or preventing all cancer cell types. The cancer treatment art involves a very high level of unpredictability. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all cancer cells in a mammal, including a human subject, with the claimed active ingredient makes practicing the claimed invention unpredictable.
Heppner et al. (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult.
Additionally, Bally et al. (US Patent No. 5,595,756) stated, "Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment limiting toxicities (See column 1).
Sporn et al. (Chemoprevention of Cancer, Carcinogenesis, Vol. 21 (2000), 525-530) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn et al. also teach that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al. (Cancer and Metastasis Reviews, 2000, 19: 167-172) indicate that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality (see p. 167, left column, 1st paragraph). Gura T (Science, 1997, 278(5340): 1041-1042) indicates that “the fundamental problem in drug discovery for cancer is that the model systems are not predictive at all” (see p. 1, 2nd paragraph). Furthermore, Gura T indicates that the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft rumors don’t behave like naturally occurring tumors in humans—they don’t spread to other tissues, for example (see p. 2, 4th paragraph). Further, when patient’s tumor cells in Petri dishes or culture flasks and monitor the cells’ responses to various anticancer treatments, they don’t work because the cells simply fail to divide in culture, and the results cannot tell a researcher how anticancer drugs will act in the body (see p. 3, 7th paragraph). Furthermore, Jain RK (Scientific American, July 1994,58-65) indicates that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain (see p. 58, left most column, 1st paragraph). Further, Jain RK indicates that to eradicate tumors, the therapeutic agents must then disperse throughout the growths in concentrations high enough to eliminate every deadly cells…solid cancers frequently impose formidable barriers to such dispersion (see p. 58, bottom of the left most column continuing onto the top of the middle column). Jain RK indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukaemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is -10%, and the cost of bringing a new drug to market is over US$1 billion.” (see page 253, left column, the 1st paragraph). Hait further teaches “The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results”, “First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value”; “Second, target overexpression is often overrated. There are some instances in which overexpression predicts response to treatment.”; and “Another confounding factor is that cancer is more than a disease of cancer cells, as alterations in somatic or germline genomes, or both, create susceptibilities to transformational changes in cells and in the microenvironment that ultimately cooperate to form a malignant tissue. The putative role of cancer stem cells in limiting the efficacy of cancer therapeutics is also an area of intense interest. Therefore, effective treatments may require understanding and disrupting the dependencies among the multiple cellular components of malignant tissues. Single nucleotide polymorphisms in genes responsible for drug metabolism can further complicate the picture by affecting drug pharmacokinetics; for example, as with the topoisomerase inhibitor irinotecan.”, for example, page 253, Section “Understanding the target in context”. Hait also teaches “Drug effects in preclinical cancer models often do not predict clinical results, as traditional subcutaneous xenografting of human cancer cell lines onto immunocompromised mice produces ‘tumours’ that fail to recapitulate key aspects of human malignancies such as invasion and metastasis. Several improvements have been made, including orthotopic implantation and use of mice with humanized haematopoietic and immune systems. Newer genetic mouse models can also allow analyses of tumour progression from in situ through locally advanced and, in certain cases, widespread metastatic disease. However, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost.”, for example, page 253, Section “Predictive models”. Furthermore, Hait teaches that “It is now widely thought that biomarkers will drive a personalized approach to cancer drug development. The aim is that they will cut costs, decrease time to approval, and limit the number of patients who are exposed to potential toxicities without a reasonable chance of benefit — as exemplified by the development of imatinib and trastuzumab. However, recent attempts at repeating these successes in other cancer types have been less successful.”, for example, page 254, Section “Stratified/personalized medicine”.
The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al (Chin Clin Oncol, 2014, 3, pages 1 -5). Gravanis et al teach “The generic mechanism of action for cytotoxics made the prediction of which tumor types might respond to them very difficult, if not impossible, and necessitated a ‘trial and error’ approach against many different types of tumors.” and “The most prominent change in oncology drug development in the last 20 years has been the shift from classic cytotoxics to drugs that affect signaling pathways implicated in cancer, which belong to the so called ‘targeted therapies’.”, for example, page 1, Section “From cytotoxics to targeted therapies: how far are we from truly personalized medicine?”. Gravanis et al. further teach “Although constantly progressing, an understanding of cancer biology is far from complete. The ability to develop new compounds or generate biological data predictive of the clinical situation relies on good quality basic research data, although the complexity and constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results. Systemic biology approaches of the -omic type still generate largely incomprehensible, mostly due to their volume, analytical data, few pieces of which are currently actionable/drug-g-able. Finally, animal models of cancer are similarly unable to predict the clinical situation (for example, page 3, right column, the 2nd paragraph).
Beans (PNAS 2018; 115(50): 12539-12543) teaches that across cancer types, 90% of cancer deaths are caused not by the primary tumor but by metastasis. Beans teaches that although some drugs may shrink metastases along with primary tumors, no existing drugs treat or prevent metastasis directly (See page 12540). Beans states “Without a targeted approach, metastatic tumors often reemerge. “We shrink them, we send them back to their residual state, and they reenact those survival functions and retention of regenerative powers that made them metastasis-initiating cells in the first place” (See page 12540). Beans teaches that one of the major scientific challenges of studying metastatic disease is that different forms of cancer seem to metastasize through different mechanisms and the same form of cancer may metastasize differently in different subsets of patients (See page 12542). Of note, Beans states “It’s unlikely that one researcher is going to find one pathway that proves to be the key to metastasis” (See page 12542). Beans also teaches that translating many findings into therapies also presents unique hurdles in that it is difficult to measure the effectiveness of the therapy. Secondary tumors are often minuscule, and therefore, measuring success by tumor shrinkage may not work. Measuring the incidence of metastasis after treatment is also more difficult (See page 12542).
Given Bally et al teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Auerbach et al teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response; Gura's teaching that the models are unpredictable; Jain's teaching that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; and Beans teachings that the field is highly underdeveloped with regards to preventing and treating cancer metastasis; the cited references demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers.
6) The amount of direction or guidance provided by the inventor; 7) The existence of working examples:
The specification teaches that serum levels of apoE in tumor-bearing apoE-/- mice inoculated with B16 (F10) melanoma cells increased progressively and considerably with tumor growth. The specification teaches that apoE-/- B16 cells lines were generated with CRISPR-Cas9 deletion. The specification teaches that apoE expression was diminished in the apoE-/- clones. The specification teaches that IFNγ production and T cell viability were significantly suppressed when T cells cultured in WT B16 CM as compared to RPMI media control. The specification teaches that apoE-/- conditioned media was similar to RPMI control media alone and did not inhibit T cell activity nor viability. The specification teaches that cell cycle distribution showed that WT conditioned media arrested activated T cells in the G0/G1 phase while apoE-/- conditioned media maintained T cells in the S phase and G2M phase of the cell cycle, similar to control media without prior exposure to tumor cells. The specification teaches that these results indicate that conditioned media derived from B16 tumor cells induces arrest pf stimulated T cells in the G0/G1 phase of the cell cycle, resulting in apoptosis and suppression of cytokine production. The specification teaches that in contrast, the singular absence of apoE in conditioned media rescues the activated T cell phenotype when stimulated with CD3/CD28 beads. The specification teaches that ten out of 27 detectable cytokines suppressed by WT conditioned media returned to baseline levels or were upregulated when T cells were cultured in apoE-/- CM. The specification teaches that COG133, a fragment of apoE peptide which competes with the apoE holoprotein for binding the low-density lipoprotein (LDL) receptors and acts as an apoE mimetic, was tested to determine its effect on T cell activation. The specification teaches that T cell viability was diminished in a dose dependent manner in T cells treated with CD3/CD28 dynabeads and COG133. The specification teaches that apoE secreted from B16 melanoma tumor cells in culture also impair activation of pro-inflammatory dendritic cells. The specification teaches that B16 WT conditioned media suppressed DC activation as determined by cytokine production, but this effect was absent in media from apoE-/- B16-F10 cells. The specification teaches that secretion of IL-10 is diminished when DC were cultured in apoE-/- CM compared to WT CM. The specification teaches that proinflammatory cytokines IL1α, IL1β, RANTES, MIP1α, and IL-28 are all increased with apoE-/- CM compared to WT CM. The specification teaches that COG133 induced secretion of IL-10 from activated DC and suppressed IL-1α, IL-1β, and IL-23 in a dose dependent manner. The specification teaches that COG133 inhibits cytokine secretion induced by immunogenic tumor cells, while anti-apoE blocking antibody enhances cytokines secretion in tumor cell/splenocyte reactions. The specification teaches that exposure of Myc-inhibited immunogenic B16 cells to COG133 repressed IFNγ production, while anti-apoE enhanced IFNγ production. The specification teaches that COG133 suppressed IFNγ production in vaccinated splenocytes co-cultured with Myc inhibited B16 tumor cells. The specification teaches that 14 out of 23 cytokines were significantly upregulated when splenocytes were co-cultured with Myc-inhibited B16 tumor cells; four of them including IFNγ, IL-6, IL-8, and RANTES were suppressed after exposure to COG133. The specification teaches that the apoE receptors lrp8 and ldlr are dominantly expressed on activated T cells and dendritic cells and blocking lrp8 enhanced T-cell activation. The specification teaches that IFNγ production from splenocytes was inhibited by COG133 in WT mice, however, the inhibitory effect was lacking in splenocytes from lrp8-/- mice. The specification teaches that T-cell function is at least partially inhibited by apoE through the lrp8 receptor pathway. The specification teaches that targeting apoE suppressed tumor growth with enhanced mouse survival in a murine melanoma model. The specification teaches that complete deletion of apoE in tumor cells and in the host cell was most effective for inhibition tumor growth, while apoE-/- B16 cells injected into WT mice or WT B16 cells injected into apoE-/- or lrp8 -/- mice partially suppressed tumor growth compared to control.
Thus, apart from a working example demonstrating that COG133 inhibited tumor growth in a mouse model of melanoma, there is no guidance regarding treating any cancer with the claimed inhibitor of apoE expression or activity. As a result, the practitioner would have to evaluate hundreds of cancer to identify cancers amenable to treatment with the claimed inhibitor of apoE expression or activity, resulting in undue experimentation.
Taken together, the art demonstrates that treatment of cancer is highly unpredictable, if even impossible for many cancers. Moreover, the art provides evidence that the heterogeneity of tumors contributes to the variability in treating cancer. Accordingly, it follows cancers that can be treated with the claimed inhibitor of apoE expression or activity can only be identified empirically. This constitutes undue experimentation. Therefore, given the lack of guidance in the art, the lack of working examples commensurate in scope to the claimed invention and the unpredictability of cancer therapy, the specification, as filed does, not provide enablement for the claimed genus of cancers.
Applying the above test to the facts of record, it is determined that 1) no declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record establishing the amount of experimentation necessary, 2) insufficient direction or guidance is presented in the specification with respect to broadly treating cancer with the claimed inhibitor of apoE expression or activity, 3) the relative skill of those in the art is commonly recognized as quite high (post-doctoral level). One of skill in the art would require guidance, in order to make or use the claimed inhibitor of apoE expression or activity to treat the vast genus of cancers in a manner reasonable in correlation with the scope of the claims. Without proper guidance, the experimentation to is undue.
The Applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including all cancers. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, determining cancers that can be treated with the claimed inhibitor of apoE expression or activity is unpredictable and the experimentation left those skilled in the art is unnecessarily and improperly, extensive and undue. See Amgen Inc v Chugai Pharmaceutical Co Ltd. 927 F 2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991) at 18 USPQ2d 1026-1027 and Exparte Forman, 230 U.S.P.Q. 546(Bd. Pat=. App & int. 1986).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph.
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 5, 13, and 15 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.
Regarding claim 5, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 13, the phrase "for example" (e.g., CAR T cell therapy) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 15, the phrase "for example" (e.g., antibody or antigen-binding fragment thereof) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 2, 4, 5, 8-13, and 16 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Vitek et al. (WO 2010/002982 A1, published January 7, 2010).
The instant claims are drawn a method for treating a cancer in a subject, wherein the cancer expresses and/or secrets apolipoprotein E (apoE), the method comprising inhibiting expression or activity of apoE, thereby treating the cancer in the subject.
Vitek et al. teach a method of treating cancer comprising administering an inhibitor of ApoE, wherein the inhibitor is an ApoE peptide (See claim 1 and paragraph 0041). Vitek et al. teach that the peptide is COG133, COG1410, COG345, COG112, or derivative thereof (See paragraphs 0023-0024 and 0033). Vitek et al. teach administering a therapeutically effective amount of the ApoE peptide (See paragraph 0010). Vitek et al. teach that cancers that can be treated with the peptide are various forms of leukemia (CLL, CML, ALL, AML), breast cancer, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, lung cancer, pancreatic cancer, brain cancer, skin cancer (melanoma and nonmelanoma), head and neck cancers, bladder cancer, endometrial cancer, renal cell cancer, thyroid cancer, stomach cancer, esophageal cancer, gall bladder cancer, liver cancer, lymphoma, and sarcoma (See paragraph 0041). Vitek et al. teach that the subject is human (See paragraph 0063). Vitek et al. teach that the peptides can be administered in combination with other therapeutic agents, such as chemotherapy agents (chlorambucil, cyclophosphamide), corticosteroids (prednisone, prednisolone), fludarabine, pentostatin, cladribine, imatinib (Gleevec), dasatinib (Sprycel), hormonal therapy (tamoxifen, aromatase inhibitors), and radiation (See paragraph 0038). Vitek et al. teach that administration of the peptide is by intravenous or subcutaneous administration (See paragraph 0044). Thus, Vitek et al. anticipate the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 4, 5, and 8-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vitek et al. (WO 2010/002982 A1, published January 7, 2010) in view of in view of Steele et al. (US Patent Application Publication 2016/0031990, published February 4, 2016).
The instant claims are drawn a method for treating a cancer in a subject, wherein the cancer expresses and/or secrets apolipoprotein E (apoE), the method comprising inhibiting expression or activity of apoE, thereby treating the cancer in the subject.
Vitek et al. teach a method of treating cancer comprising administering an inhibitor of ApoE, wherein the inhibitor is an ApoE peptide (See claim 1 and paragraph 0041). Vitek et al. teach that the peptide is COG133, COG1410, COG345, COG112, or derivative thereof (See paragraphs 0023-0024 and 0033). Vitek et al. teach administering a therapeutically effective amount of the ApoE peptide (See paragraph 0010). Vitek et al. teach that cancers that can be treated with the peptide are various forms of leukemia (CLL, CML, ALL, AML), breast cancer, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, lung cancer, pancreatic cancer, brain cancer, skin cancer (melanoma and nonmelanoma), head and neck cancers, bladder cancer, endometrial cancer, renal cell cancer, thyroid cancer, stomach cancer, esophageal cancer, gall bladder cancer, liver cancer, lymphoma, and sarcoma (See paragraph 0041). Vitek et al. teach that the subject is human (See paragraph 0063). Vitek et al. teach that the peptides can be administered in combination with other therapeutic agents, such as chemotherapy agents (chlorambucil, cyclophosphamide), corticosteroids (prednisone, prednisolone), fludarabine, pentostatin, cladribine, imatinib (Gleevec), dasatinib (Sprycel), hormonal therapy (tamoxifen, aromatase inhibitors), and radiation (See paragraph 0038). Vitek et al. teach that administration of the peptide is by intravenous or subcutaneous administration (See paragraph 0044).
Vitek et al. do not teach wherein the second anti-cancer therapy is an immune checkpoint inhibitor.
Steele et al. teach a pharmaceutical composition comprising an anti-PD-L1 antibody (See paragraphs 0012-0016 and 0051). Steele et al. teach that the anti-PD-L1 antibody is MEDI-4736 (See paragraph 0069). Steele et al. teach that the composition is useful for treating cancer, such as head and neck cancer, lung cancer, NSCLC, oropharyngeal squamous cell carcinoma, breast cancer, and melanoma (See paragraphs 0012, 0115, and 0142).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Vitek et al. to include the checkpoint inhibitor anti-PD-L1 because Steele et al. teach that anti-PD-L1 is also useful for treating cancer. One of ordinary skill in the art would be motivated to treat cancer comprising administering a combination of an ApoE peptide inhibitor and a checkpoint inhibitor because each of the therapies have been individually taught in the prior art to be successful for treating cancer. Moreover, the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the very same purpose. The idea of combining them flows logically from having been individually taught in the prior art. Applying the same logic to the instant claims, one of ordinary skill in the art would have been imbued with at least a reasonable expectation of success that by administering an ApoE peptide inhibitor in combination with a checkpoint inhibitor as taught in Vitek et al. in view of the teachings of Steele et al., one would achieve a composition for treating cancer. The use of the claimed ApoE peptide inhibitor and in combination with a checkpoint inhibitor to treat cancer is nothing “more than the predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results". The combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 4, 5, 8-10, and 12-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 11, 14, 35, 36, 38, 39, 42 and 43 of copending Application No. 17/425, 130 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a method of treating cancer comprising administering an apoE inhibitor and further comprising administering a checkpoint inhibitor.
The ‘130 claims teach a method of treating cancer comprising administering cancer cells and at least one checkpoint inhibitor to the subject, wherein the checkpoint inhibitor is selected from the group consisting of programmed cell death-ligand 1 (PD-Li) inhibitors and cytotoxic T- lymphocyte-associated protein 4 (CTLA-4) inhibitors, wherein said PD-Li inhibitor is atezolizumab, avelumab, or durvalumab, and wherein said CTLA-4 inhibitor is ipilimumab, thereby treating said cancer, wherein said cancer is neuroblastoma or melanoma. The ‘130 claims teach wherein the checkpoint inhibitor is an anti-PD-L1 inhibitor and an anti-CTLA-4 inhibitor. The ‘130 claims teach further comprising administering an inhibitor of ApoE, wherein said inhibitor of ApoE is APX3330, APX2009, or APX2014. Thus, the ‘130 claims anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Status
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA CARTER whose telephone number is (571)272-2932. The examiner can normally be reached 8:00-5:00 pm.
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/SANDRA CARTER/ Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
