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 .
Claim Status
Claims 1-17 are under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
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.
The information disclosure statement (IDS) submitted on 11/29/2022 is being considered by the examiner.
Drawings
The drawings are objected to because Fig. 10f is not legible.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The name of the parent active agent let-a should be in the title in some way.
The use of the terms ALAMARBLUE (Pg. 5), RNEASY (Pg. 10) and QUANTI-BLUE (Pg. 17), each of 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 Objections
Claim 17 is objected to because of the following informalities: The final “from” in the penultimate line should be changed to “of”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-6, 10-12 and 16-17 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.
Claim 2 recites 80% sequence identity to SEQ ID NO: 1 or the RNA molecule of claim 1 for use as a medicament. This language gives the claim and its dependents multiple interpretations. First, 80% identity could modify both SEQ ID NO. 1 and the RNA of claim 1. Second, the identity requirement may only modify SEQ ID NO. 1. The presence of multiple structural interpretations renders the claims reciting the same indefinite.
Claim 16 depends on claim 6 which is indefinite for the reason above. However, claim 16 has itself multiple interpretations. First, it may require the RNA molecule of claim 6. Second, it may be any RNA molecule but require only the use of claim 6. The presence of multiple interpretations renders the claim indefinite. This same rejection is made for claims 4-6 also.
Claims 6, 12 and 16-17 all recite incubation with cell extracts. This phrase has a special definition in the specification at page 13. There, it states that incubating with cell extracts refers to a process in which cells are first homogenized in extraction buffer with protease and phosphatase inhibitors. The definition stops. There are two other steps that follow in the same paragraph but they are not part of the definition. Thus, the claims may require only the steps of the definition above and any in the claims. They may require instead all three steps of the paragraph on page 13 as well as any in the claims. The presence of multiple interpretations renders the claims indefinite.
Claims 10-12 and 17 recite the RNA fragments. There is insufficient antecedent basis for such structures in the claims and so it is not clear which fragments are being referred to. Thus, the claims are indefinite and rejected here.
Claims 6 and 16 also recite the treatment of claim 2. However, there is no antecedent basis for a treatment step in claim 2 and so the scope of these two claims is unclear.
See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 2-6, 10, and 15-16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 recites an embodiment in which the RNA molecule of claim 1 is used as a medicament. Intended use of a structure is not given patentable weight. Therefore, this embodiment of claim 2 fails to further limit the claim on which it depends claim 1. The same rejection is made for claims 3-6 and 15-16. Claim 6 contains an embodiment in which the cell extract incubation is part of the intended use of claim 2 and therefore, claim 6 fails to further limit claim 2. The same rejection is made for claim 16, which fails to further limit claim 6 for the same reason.
Claim 4 contains a list of cancers allegedly and claim 3 on which it depends recites the genus cancer. However, aplastic anemia is not a cancer and so does not further limit the cancer of claim 3 on which claim 4 depends. Thus, claim 4 is rejected here for this reason also.
Claim 10 recites products by process after claim 7 on which it depends already sets forth the structures encompassed. Thus, claim 10 does not structurally change the RNA molecule of claim 7, failing to further limit the claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form so long as no duplicates are made, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for isolated RNA molecules comprising SEQ ID NO. 2 or the truncate thereof leta80, does not reasonably provide enablement for similar molecules that are not isolated and so can be present in a transgenic animal or that have just 80% identity to SEQ ID NO.2 which includes truncations and mutations of the parent molecule not demonstrated to cause apoptosis of target cells. Furthermore, not just any cancer would be expected to be treatable with SEQ ID NO. 2 or any functional variant thereof. 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 or use the invention commensurate in scope with these claims.
The breadth of the claims is found in claim 1 drawn to an RNA molecule having a sequence at least 80% identical to SEQ ID NO. 2.
The nature of the invention is a single stranded RNA that binds TLRs, inducing apoptosis in target cells, including cancer cells.
The level of skill of one skilled in this art is high.
The specification teaches let-A from Drosophila is toxic to some mammalian cells whether it is transfected into said cells or given extracellularly thereto (Pg. 27, Example 5). Let-A is instant SEQ ID NO. 2 (Pg. 8). This appeared to occur in part via TLR3 activation (Pg. 28). Example 7 on page 29 presents leta80 which lacks the final 20% at the 3’ end of let-A. Figure 11B shows this variant can also induce cell death. Other mutants were made but not taught by sequence. See example 7. Indeed, only 2 sequences reside in the sequence listing. The cell lines tested for let-A-induced cytotoxicity included HeLa, C2C12 myoblast, Mcf7, Bt8A, and K562 (Example 5, page 27). Figure 8B shows all those were killed by let-A treatment. These cells, with respect to those that are a cancer line, are cervical cancer, breast cancer, glioblastoma, and CML. The lower half of Figure 8B demonstrates that let-A is not toxic to just any cell type. Thus, it is only predictable that Applicant can treat cervical and breast cancer, CML and glioblastoma with let-A.
With respect to the scope of the RNA molecule recited in the claim, it encompasses any variant with 80% identity to SEQ ID No. 2. No one sequence need be maintained therefore. It is also not clear all the TLRs that play a role in the anti-cancer mechanism. TLR3 appears to be at least one. However, it is unclear that TLR3 can even be activated by the full scope of RNA molecules encompassed here, even if one assumed such activation were sufficient to yield therapeutic effect, which one of skill in this art would not barring actual evidence. The art is well aware that TLRs require specific features of their ligands to function. Therefore, as broadly as the RNA of instant claims is recited, it is not enabled to its full scope to have any function.
Li (eLife, Vol. 1, e00102, Pg. 1-14, 2012) teaches TLR13 requires a sequence of 13 nucleotides that is necessary for TLR13 signaling (Abstract). Even single point mutations in this sequence destroyed TLR13 activation (Abstract). Shimizu (Current Opinion in Structural Biology, Vol. 88, No. 102913, Pg. 1-8, 2024) teaches that TLR3 is a double stranded RNA (dsRNA) sensing TLR (Pg. 2, Columns 1-2, last two paragraphs). Therefore, it appears to need a type of quaternary structure but lacks base specificity (Pg. 4, Paragraph, first). They state that 40-50 bp length is sufficient for binding but 90 or more bases is required for some cell signaling (Pg. 2-3, Paragraph, spanning). TLR3 dimer clustering improves signaling (Pg. 4, Columns 1-2, Paragraph, spanning). Meanwhile TLR7 requires a polyU sequence (Pg. 4, Paragraph, penultimate). Zhang (Cell Reports, Vol. 25, Pg. 3371-3381, 2018) teaches TLR7 binds ssRNA and guanosine (Abstract). However, the ssRNA should have successive uridines since those with single uridine have reduced affinities (Abstract). They further show in Figure 1I that sequence variation and guanosine presence greatly affects TLR7 signaling. Yet, it is not possible to predict the true amplitude of signaling without testing. This demonstrates that PHOSITA cannot envision the functionality of any untested let-A variant encompassed by the instant claims. It is noted that both TLR3 and TLR7 are intracellular in general found in the endosomal compartment with TIR domain facing the cytoplasm, requiring their targets to be in the endosomal vesicle. For support of this, see Vierbuchen (Allergy, Vol. 74, Pg. 223-235, 2019) at Pg. 225, Paragraph, first and in Figure 1. Thus, there are other mechanisms required in the instant case for extracellular RNA to arrive at these two TLRs. Furthermore, thought TLR3 may play some role with SEQ ID NO. 2, Applicant teaches it as a long non-coding RNA and not as a double stranded RNA. They state it is preferably single stranded (Pg. 8). These provide concerns that the full mechanism of the anti-cancer effect is not known and taken all together, it is clear that PHOSITA cannot predict the functioning of any SEQ ID NO. 2 variant other than those shown by Applicant to have an anti-cancer effect. This includes only SEQ ID NO. 2 (let-A) and one truncate thereof (leta80). As broadly as currently claimed, the RNA molecule of instant claims with 80% identity to SEQ ID NO. 2 is not enabled.
With respect to treating just any cancer, Applicant has only shown efficacy against four cancers as discussed above. Also as mentioned supra, the mechanisms of let-A action have not been completely elucidated. Therefore, it is not sufficient for the target cell to express one target protein, for example. It is not clear that only one target protein is sufficient and necessary for the anti-cancer action. Without knowing the nexus between let-A action and cancer cell death, Applicant is only enabled to treat cancers they have shown are sensitive to let-A.
Cancer treatment is highly unpredictable. Even though the EGFR was identified in some cancers as a drug target, the in vitro (i.e., in a test tube) effectiveness of a drug in inhibiting the EGFR turned out to be a poor proxy for how effective that drug actually was in treating cancer in vivo (i.e., in the body). Numerous EGFR inhibitors that showed promising in vitro activity failed for a variety of reasons. These included poor pharmacokinetics due to poor absorption or rapid metabolism ( [**2]or both), undesirable drug-drug interactions, drug toxicity due to drug binding onto healthy cells, drug toxicity due to binding onto other receptors, and metabolite toxicity. Some drug candidates were limited by one or more of these shortcomings, further underscoring the unpredictable nature of cancer treatment. OSI Pharmaceuticals , LLc, v. Apotex Inc, 939 F.3d 1375, 2019.
The state of the art at the time of filing was such that the functionality of an anti-cancer agent, such as an anti-tumor antibody, was dependent on both its action on the intended target and whether or not the modulation of said target had an effect on any particular cancer cell. Baxevanis (Expert Opinion: Drug Discovery, Vol. 3, No. 4, Pg. 441-452, 2008) teaches that, depending on the epitope against which an antibody is directed, antibody-antigen binding may neutralize circulating targets or cell surface receptors (Pg. 444, Column 1, Paragraph, first full). They teach that presently available monoclonal antibodies (mAbs) are directed against molecular targets that are expressed on tumor cells or play an important role in the tumor microenvironment (Pg. 444, Column 1, Paragraph, first full; Table 1). Table 1 lists currently available antibodies for use in clinical oncology and illustrates that each antibody has a specific target (Table 1, Column 2) and a specific set of cancers for which it has therapeutic utility (Table 1, Column 4). Taken together, the art does not recognize a single antibody that is an effective therapy against all tumors. The same can be said for any anti-cancer agent; not one is a magic bullet.
The teachings of Baxevanis discussed above underline the requirement of a link between a cancer therapeutics mechanism of action and specific cancers to make therapy of said cancer predictable to one of ordinary skill in the art. The prior art is silent as to the use of SEQ ID NO. 2 against any cancer and so all enablement must come from the instant specification. Therefore, Applicant only enables use of let-A and leta80 against cancers that they show are killed by treatment with the same.
Lastly, unisolated RNA molecules can be found within cells of transgenic animals. To produce them, that animal must have a functional transgene that expresses instant SEQ ID NO. 2 stably while surviving. Yet, let-A is cytotoxic to some cell types including some that are not cancerous like myoblasts. This raises doubt, given transfection of it into cells can kill them that a transgenic animal can be made therewith. Applicant produced none. Thus, as broadly as currently claimed, all unisolated RNA molecules are not enabled to their full scopes.
With respect to the unisolated RNA molecules encompassing those produced from transgenes in a transgenic animal, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et Al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et Al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et Al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce let-A and variants thereof as in the instant claims.
At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable and even if a transgenic cell could be made to produce let-A, it is unpredictable that it would evolve into a living animal with any reasonable lifespan as to be commercially viable. The claims as written, encompassing RNA from a transgene in a transgenic animal, are not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to recite the term "isolated" before the recitation, "RNA" in all cases. Applicant may consider using purified in the claims if description is appropriate for such a term and it is not redefined away from standard meaning.
Of note, all the same arguments above are made against all recitations of an RNA molecule from a DNA sequence of 80% identity to SEQ ID NO. 1 of the instant claims since this would result in unpredictable RNAs discussed above.
Claims 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims above are drawn to a genus of RNAs based on the parent molecule let-A (SEQ ID NO. 2). Several claims contain additional functional language such as their use against cancer. No claim requires a specific sequence across all species of the genus. When one goes to the instant specification to identify a representative number of species to define the claimed genus by either structure or structure and the required function above, they find only two species SEQ ID NO. 2 and a single truncate thereof leta80 missing the last 20% of the parent. Additional species were allegedly made. Example 7 on page 29 presents leta80 which lacks the final 20% at the 3’ end of let-A. Figure 11B shows this variant can also induce cell death. Other mutants were made but not taught by sequence. See example 7. Indeed, only 2 sequences reside in the sequence listing. Thus, Applicant attempts to represent a genus with only two functional species. The prior art is silent to species within this genus.
“[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.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus, Applicant must adequately describe representative RNAs to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that 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, 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 applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the RNAs have no conserved sequence, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any other RNA species with utility and the required function in some claims (anti-cancer agent) other than the two species provided by Applicant. Therefore, since only two species is provided to represent the genus, the claims encompassing the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “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 one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). There is no correlation between structure and function between the members of the claimed RNA genus as any residue can be varied and, as discussed in the enablement rejection above, incorporated here in its entirety, the anti-cancer mechanisms of the claimed molecules have not been fully elucidated sch that PHOSITA would even know which TLRs, or other proteins, are necessary and sufficient to cause the anti-tumor effect.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. Two species is certainly not adequate.
Overall, at the time the invention was made, the level of skill for preparing RNAs and then selecting those with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify RNAs with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”)
Since only two species are taught within the claimed genus above, those with 80% identity to let-A, all with utility including anti-cancer properties, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe the genus. Though Applicant alleges to have made and shown other variants work against cancer cells, they have not taught the sequences of these variants and so such are not described by required partial structure or full structure. Given that the mechanism of let-A is not completely known and TLRs do not bind just any RNA molecule nor do they signal in response to just any such molecule, one of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. The size of the genus far outweighs Applicant’s contribution of two sequences.
Any future RNA structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that "[w]ithout such disclosure, the claimed methods cannot be said to have been described."). Thus, the described species cannot be considered representative of the recited huge genus of RNA molecules claimed, including those with anti-cancer effects. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing "a result that one might achieve if one made that invention"); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite only the full sequence of a functional RNA molecule taught.
Of note, the same arguments are made against all recitations of an RNA molecule from a DNA sequence of 80% identity to SEQ ID NO. 1 of the instant claims since this would result in the genus discussed above.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product/judicial exception without significantly more.
The claim(s) recite(s) the RNA molecule SEQ ID NO. 2. This is let-A of the instant application (Pg. 8). It is a natural product as discussed in the specification at pages 22-23. There, it teaches that the let-7-C locus of Drosophila encodes two lncRNA, one of which is let-A. These pages make clear that this RNA is expressed naturally during development. Thus, SEQ ID NO. 2 is a natural product and the claims must be evaluated for significantly more.
Of note, claims 1-6 require only this RNA molecule and no other structures. The claims differ only but intended uses that receive no weight. The same can be said for claim 16.
Other claims require the RNA be in a pharmaceutical composition which would encompass the RNA found in its natural context surrounded by aqueous solution. Thus, claims 7-8 and 10 read on natural products. Claim 9 also so reads as it requires only fragments of the natural products above. Thus, it is sequences found in the natural product only plus aqueous solution. Claim 11 requires encapsulation and the natural lncRNA residing in a cell or endosome (where the targets of TLR3 and TLR7 reside) meets these structural limitations and so it too reads on a natural product. Exosomes are just endosomes that have left a cell. Claim 12 is also natural as the lncRNA is found in cells and so natural exposed to their contents. Claim 13 equally reads natural products as it reads on the natural locus discussed above which meets the structural limitations of this claim. There is no definition of vector in the specification and so the natural locus having all its regulatory elements meets this limitation as it contains all the elements required of a vector. Said locus is an analog (analogous to) a plasmid and so claim 14 reads on a natural product. Claims 15 and 17 also read on natural products for the reasons above having a use with no weight or reading on the RNA in natural context, being exposed to intracellular space. Again, all composition claims require only the natural structures of the RNA or its DNA locus and water, for example. Thus, all claims read on natural products.
This judicial exception is not integrated into a practical application because there is no method step or additional structural element that modifies the structure claimed away from natural products. Thus, there is no element that prevents a monopoly over these natural products.
The claim(s) do not include additional elements that are sufficient to amount to significantly more than the judicial exception because every element of the claims is part of a natural product for the reasons above. There are no additional elements required in all embodiments that affect the structure or function of the natural product or amount to more than what is already well-understood, routine, and conventional.
Taken all together, the claims are patent ineligible and rejected here.
Conclusion
No claim is allowed.
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/Michael Allen/Primary Examiner, Art Unit 1642