Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 131-150 are pending and under consideration.
Claim/Specification Objections
Claims 135, 141 and 150 are objected to because of the following informalities:
Claim 135 recites “chemotherapeutic agent” twice in the Markush grouping.
Claim 141 (and the specification-[0094]) comprises a Markush grouping of different nonpropriety-named antibodies. However, some of these antibodies appear to be duplicated. For example, a search for NEOD001 indicates that it is also referred to as “birtamimab”. Similarly, the claimed TNX-650 is also named “lebrikizumab” and IMAB362 is “zolbetuximab”. Applicant is requested to check for other duplicates and amend the claims and specification appropriately.
Claim 150 is objected to for reciting “or antigen binding fragment thereof, “in” an anti-ICAM” as it appears the word “in” should be “is”.
Appropriate corrections are requested.
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.
Claim 140 contains the trademark/trade name NANOBODY. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a type of antibody or antigen-binding fragment thereof and, accordingly, the identification/description is indefinite.
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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 131-150 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. This is a Written Description rejection.
Claim 131 is broadly drawn to a method of treating any and all diseases in a subject in need thereof comprising administering an antibody conjugated to an oligonucleotide wherein: the conjugate binds an antigen to a greater extent or faster compared to its unconjugated equivalent antibody and wherein the conjugate has a faster clearance from the blood of the subject compared to its unconjugated equivalent and wherein the antibody conjugate is not hybridized to a dendrimer. Claim 142 states that the oligonucleotide can comprise a “non-natural” or “modified” oligonucleotide or that it may comprise a nucleotide “analog” or “substitute”. All of the latter may further comprise (Claim 143) modified bases, modified sugars, or modified phosphate groups.
In terms of diseases to be treated, the specification does not provide any limitations of the types of diseases to be treated. For example, the specification discloses [0122-0127] that the conjugated antibodies may be used to treat various antigen-expressing neoplasms. In some embodiments, the antibodies, or antigen-binding fragments thereof, described herein can be used to treat antigen-expressing cancers, such as sarcomas with properties of skeletal muscle, and skin tumors. In some embodiments, the antibodies, or antigen-binding fragments thereof, can be used to treat antigen-expressing neurological cancers, such as a brain tumor or a small brain lesion, such as micro-metastases, in a patient. Other types of cancer that may be treated include breast, ovarian, prostate and kidney. The specification also teaches [0142-0143] that fibrosis and Posterior Capsule Opacification can be treated.
In terms of the genus of oligonucleotides that can be conjugated to antibodies, the specification identifies many possible structures. For example, the oligonucleotides disclosed [0146] can comprise nucleotides or non-natural, or modified nucleotides, such as nucleotide analogs or nucleotide substitutes. Such nucleotides include a nucleotide that contains a modified base, sugar, or phosphate group, or that incorporates a non-natural moiety in its structure. Examples of non-natural nucleotides include, but are not limited to, dideoxynucleotides, biotinylated, aminated, deaminated, alkylated, benzylated, and fluorophore-labeled nucleotides. The oligonucleotides can comprise DNA, RNA, or both DNA and RNA.
The specification fails, however, to describe the genus or show possession of a representative number of species of diseases that can be treated as broadly claimed. Further, the specification fails to describe the genus or show possession of a representative number of antibodies conjugated to oligonucleotides with the claimed functional properties: binds an antigen to a greater extent or faster compared to its unconjugated equivalent antibody and wherein the conjugate has a faster clearance from the blood of the subject compared to its unconjugated equivalent.
A "representative number of species" means that the species, which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus."). In the instant case, it’s not clear that the specification teaches any structural species with the claimed functional activity. For example, the specification teaches [0161] that antibody-oligonucleotide (Ab-oligo) conjugations for anti-ICAM or non-specific control IgG Abs were performed using N-hydroxysuccinimide (NHS)-maleimide chemistry. A 72-mer DNA oligonucleotide with a 5′-thiol modification appears to have been used. But the specification does not distinctly define the structure of this 72-mer species. It cannot be confirmed that this structure is SEQ ID NO:1 (Claim 149) because the specification does not explicitly state that they are one in the same. Further, the examples disclosed only generically speak to a “antibody-oligonucleotide” conjugate without disclosing the structure of the oligonucleotide or the degree of conjugation. For example, when discussing circulation and biodistribution, the specification teaches [0164] that anesthetized C57BL/6 mice were injected with 123I-labeled antibodies or antibody-oligonucleotide conjugates. Or, when describing Figure 3, the specification states [0167] that FIG. 3 shows anti-ICAM-oligonucleotide is rapidly removed from the bloodstream. Mice were injected intravenously with non-specific IgG control antibody, ICAM-1 specific anti-ICAM antibody, or anti-ICAM-oligo conjugate (Panel A), or anti-ICAM-oligo or IgG-oligo conjugates.
Even if it’s confirmed that SEQ ID NO:1 is one of the oligo conjugates with the claimed functional property, the disclosure of only one species encompassed within a genus only adequately describes a claim directed to that genus if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.).
In the instant application, the specification fails to adequately disclose a single structural species of antibody-oligonucleotide conjugates with the claimed functional properties. Dovgan et al. (Bioconjugate Chemistry, Vol. 30, Issue 10, July 24, 2019) discusses the state of the art regarding antibody–oligonucleotide conjugates as therapeutic, imaging, and detection agents. They state (page 2484, 2nd column) that one of the important characteristics of bioconjugates is the degree of conjugation (DoC) representing the number of oligonucleotides molecules per antibody. The average DoC value can be found using MS analysis or gel electrophoresis. The DoC value directly defines the molecular weight and size of the AOC (antibody oligo conjugate) and is therefore responsible for such physicochemical properties as solubility, affinity, and aggregation. Moreover, the significant negative charge of oligonucleotides has an important impact on the antibody, which is positively charged at neutral pH. The overall charge of the conjugate species is therefore proportional to the DoC values. In the instant case, it does not appear that the specification identifies the degree of conjugation of the claimed antibody conjugates with the claimed functional activity. Further, in terms of the claimed functional activity, the specification appears to teach [0018] that such activity was unusual and unexpected:
“In addition, antibody-oligonucleotide conjugates were cleared from the circulation in mice faster than regular antibodies and were distributed more profusely, which may serve to avoid systemic side effects of antibodies applied to the human body. This observation was surprising since coupling to an oligonucleotide would be expected to lower the binding and/or targeting ability of the antibody because of: a) steric hindrance, b) possible modification or interference with the variable region which recognizes the antigen, c) changes in the physicochemical properties of other antibody regions, and/or d) the negative charge provided by the oligonucleotide (nucleic acids are negatively charged species) that would repel the negative charge present on the surface of cells in the body (provided by sugar moieties of glycosylated proteins and lipids in the cellular membrane). The mechanism for this unexpected finding is unknown; nevertheless, the finding holds significant translational potential.” [0018]
Therefore, the specification does not describe a representative number of species which fall within the context of the currently drafted claims
It has been well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression and activities. Based on the instant disclosure one of skill in the art would not know which structures are essential for providing a greater extent or faster binding to an antigen while also providing for a faster clearance from the blood. Mere idea or observation of function in the absence of technical structural details is insufficient for written description; isolation and characterization at a minimum are required.
In the absence of sufficient guidance, direction, and disclosure of the claimed antibody oligonucleotides with the claimed functional properties, the specification as filed does not appear to provide sufficient written description for the genus as broadly claimed. For inventions in an unpredictable art, adequate written description of a genus, which embraces widely variant species cannot be achieved by disclosing only one (or none) species within the genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states "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). As discussed above, the skilled artisan cannot envision the detailed structure of the encompassed genus of antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiefs v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v.Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, 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.
No claim is allowed.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Roki et al. (Jnl Controlled Release, 305, May 2019) appear to teach aspects of the claimed invention but do not indicate or render obvious that any particular disease may be treated.
20230049529 (Kel’in et al. priority to 06-18-202) is directed to dual variable domain immunoglobulin double-stranded RNA conjugates that are advantageous for inhibition of target gene expression, as well as compositions suitable for therapeutic use. Kel’in et al. does not appear to teach rapid clearance from the blood.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643