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 .
Improper Markush Rejection
Claims 20 and 21 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The claims recite the Markush group “an aptamer or variant thereof, an oligonucleotide, an antisense oligonucleotide, CpG, siRNA, shRNA, microRNA, lncRNA, mRNA, antisense RNA, saRNA., circular RNA and the like’. Antisense oligonucleotides function by recruiting RNase H to cleave the RNA strand, preventing translation to protein. In contrast, siRNAs do not recruit RNase H, but instead bind to Argonaute proteins and function to guide those proteins to targets. Accordingly, siRNAs and antisense oligonucleotides do not have sufficiently similar structures to provide the same function because each has a structure that dictates its pathway of action. Each of the agents have different structures and/or act via different mechanisms.
Accordingly, each of the agents do not have sufficiently similar structures to provide the same function because each has a structure. Therefore, the members of the Markush group lack any common substantial structural feature that provides a common use, and the group of alternatives is an improper Markush group. In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. 134 and 37 CFR 41.31(a)(1).
As instantly drafted, claim 1 link(s) the inventions of the claims. The restriction requirement among the linked inventions is subject to the nonallowance of the linking claim(s), claim 1. Upon the allowance of the linking claim(s), the restriction requirement as to the linked inventions shall be withdrawn and any claim(s) depending from or otherwise including all the limitations of the allowable linking claim(s) will be entitled to examination in the instant application. Applicant(s) are advised that if any such claim(s) depending from or including all the limitations of the allowable linking claim(s) is/are presented in a continuation or divisional application, the claims of the continuation or divisional application may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Where a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. In re Ziegler, 44 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
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 20, 35, and 36 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 20 is directed to a genus of nucleic acid molecules and “the like”. The metes and bounds of “the like” cannot be clearly ascertained and therefore the claim language is not definite. The language does not impart any meaningful structural limitation.
Claims 35 and 36 recite nucleic acid sequences “presented by” the recited SEQ ID NO. It is unclear whether “presented by” is intended to be equivalent to “consisting” or “comprising” or some other meaning. A 2 nucleotide fragment of the entire sequence of SEQ ID NO: 1 meets the instant limitation of a nucleic acid sequence presented by SEQ ID NO: 1, for example. The claims are therefore indefinite.
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 20 and 21 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.
Claim 20 is directed to “a therapeutic nucleic acid” including any of the listed types or the like. The specification does not adequately describe the genus of therapeutic nucleic acids. Without further knowledge of the structure required for the function, one would not be able to readily recognize which nucleic acids are necessarily therapeutic.
The claims recite an aptamer of a variant thereof. The specification does not adequately describe the structure required for a compound to be a variant of an aptamer and function as required. The aptamer species of the specification are not representative of the entire claimed genus. The specification does not disclose any variants of aptamers. Without further description of the structure required for the function, one would not be able to readily envision which nucleic acids meet the limitation of being a variant of an aptamer.
Additionally, the specification does not adequately describe nucleic acid molecules that are “like” each of the recited species of nucleic acids. The species disclosed are not representative of the entire claimed genus and the specification does not describe the structure required for agents to be “like” each of the species. Without further description of the structure required for the function, one would not be able to readily envision which nucleic acids meet the limitation of being like each of the recited types of nucleic acids.
The MPEP states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. See MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618. Additionally, in Carnegie Mellon University v. Hoffman-La Roche Inc., Nos. 07-1266, -1267 (Fed. Cir. Sept. 8, 2008), the Federal Circuit affirmed that a claim to a genus described in functional terms was not supported by the specification’s disclosure of species that were not representative of the entire genus. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The Guidelines for Examination of Patent Applications under the 35 USC § 112, first paragraph, “Written Description” Requirement”, published at Federal Register, Vol. 66, No. 4, pp. 1099-1111 outline the method of analysis of claims to determine whether adequate written description is present. The first step is to determine what the claim as a whole covers, i.e., discussion of the full scope of the claim. Second, the application should be fully reviewed to understand how applicant provides support for the claimed invention including each element and/or step, i.e., compare the scope of the claim with the scope of the description. Third, determine whether the applicant was in possession of the claimed invention as a whole at the time of filing.
With respect to siRNAs, a single recited species, Elbashir et al. (The EMBO Journal, Vol. 20, No. 23, pages 6877-6888, 2001) teaches that duplexes of 21-23 nt RNAs are the sequence specific mediators of RNAi and that even single mismatches between the siRNA duplex and the target mRNA abolish interference (abstract and page 6888). Therefore, one would not be able to recognize which agents are like siRNAs and function as needed.
Stein (The Journal of Clinical Investigation, 2001, 108, 5, 641-644) teaches that if the antisense oligonucleotide is either too long or too short, an element of specificity is lost. At the present time, the optimal length for an antisense oligonucleotide seems to be roughly 16–20 nucleotides (page 641). Therefore, one would not be able to recognize which agents are like antisense oligonucleotides and function as needed.
Thus, having analyzed the claims with regard to the Written Description guidelines, it is clear that the specification does not disclose a representative number of species for the recited nucleic acids within the instant enormous genus that function. Thus, one skilled in the art would be led to conclude that Applicant was not in possession of the claimed invention at the time the application was filed.
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, 7, 20, 21, and 24 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Shen (WO 2021/046497 A2).
Shen teaches a conjugate comprising a nucleic acid moiety and a fatty acid moiety, wherein the fatty acid moiety is conjugated to the end of the nucleic acid moiety and the fatty acid moiety comprises –(CH2)a-COOH, wherein a is 12-26 ([0074]-[0078], [0109], Example 8, pages 44-45, miRNA conjugated to LCFA, Figure 17A)( –(CH2)15-COOH). The miRNA meets the instant limitation of being a variant of an aptamer (instant claims 1, 7, 20, 21, and 24).
Shen teaches: This disclosure is directed to a pharmaceutical composition comprising a bioactive agent (active pharmaceutical ingredient, API) and at least one long chain fatty acid (LCFA), wherein the long chain fatty acid can comprise a carbon chain having at least 10 carbon atoms and can comprise a free carboxylic acid group or a salt thereof. The LCFA-conjugated active pharmaceutical ingredient (API) can be resistant to acid degradation in digestive system and facilitate the delivery of the API across the small intestinal epithelial cell membrane via fatty acid transport protein 4 (FATP4, also known as SLC27A4). The pharmaceutical composition can be formulated in acid- resistant (enteric-release) dosage forms for oral administration in patients. This disclosure is further directed to a process for producing the LCFA-conjugated bioactive agent including protein, polypeptide, small molecule drugs, DNA, RNA, oligonucleotide, or a combination thereof (abstract).
Therefore, the claims are anticipated by Shen.
Claim(s) 1, 2, 4, 6, 7, 10, 18, 20, 21, 24, and 30 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Roloff et al. (WO 2018/175592 A1).
Roloff et al. teach: The present disclosure generally provides nucleotide-based compounds useful for treating various diseases, including cancer. In some aspects, the disclosure provides oligonucleotides that are chemically modified to include an engineered fatty-acid residue, for example, to assist with improving the half-life of such compounds or assisting with cell penetration (e.g., penetration into tumor cells). In some aspects, the disclosure provides compositions that include such modified nucleotides and a protein, such as albumin or mimetics thereof. The disclosure provides various uses of the compounds and compositions (abstract)(page 7) (instant claims 1, 20, 21, and 24). The oligonucleotide meets the instant limitation of being a variant of an aptamer.
The structure taught in the abstract is:
PNG
media_image1.png
148
346
media_image1.png
Greyscale
Roloff et al. teach incorporation of NH-CO (pages 2, 13, and 21) (instant claim 7), carboxyl groups (pages 2, 14, and 21) (instant claim 2), an ethylene glycol group (pages 17 and 21), siRNAs (pages 19 and 20), miRNAs (page 20), compounds HB1-HB16 (pages 20-21), compounds HA1-HA4 (pages 21 and 22)(instant claims 18 and 30), pharmaceutical preparations (page 22)(instant claim 24), and ODDA-conjugated siRNAs (page 30) (instant claims 20 and 21).
Roloff et al. teaches that the nucleic acid to be conjugated is a siRNAs, miRNA, or antisense sequence (claim 8). Roloff et al. teach incorporation of a PEG group or ethylene glycol units (instant claims 4 and 6). Roloff et al. teaches incorporation of a glutamic acid group (instant claim 10).
Therefore, the claims are anticipated by Roloff et al.
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, 6, 7, 10, 11, 14, 15, 18-21, 24, 25, 27, 30, and 34-36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shen (WO 2021/046497 A2), in view of Roloff et al. (WO 2018/175592 A1), Suckow et al. (WO 2021/108662 A1), Grinstaff et al. (US 12,281,161 B2), and Zhu et al. (WO 2021/158583 A1).
Shen teaches a conjugate comprising a nucleic acid moiety and a fatty acid moiety, wherein the fatty acid moiety is conjugated to the end of the nucleic acid moiety and the fatty acid moiety comprises –(CH2)a-COOH, wherein a is 12-26 ([0074]-[0078], [0109], Example 8, pages 44-45, miRNA conjugated to LCFA, Figure 17A)( –(CH2)15-COOH). The miRNA meets the instant limitation of being a variant of an aptamer (instant claims 1, 7, 20, 21, and 24).
Shen teaches: This disclosure is directed to a pharmaceutical composition comprising a bioactive agent (active pharmaceutical ingredient, API) and at least one long chain fatty acid (LCFA), wherein the long chain fatty acid can comprise a carbon chain having at least 10 carbon atoms and can comprise a free carboxylic acid group or a salt thereof. The LCFA-conjugated active pharmaceutical ingredient (API) can be resistant to acid degradation in digestive system and facilitate the delivery of the API across the small intestinal epithelial cell membrane via fatty acid transport protein 4 (FATP4, also known as SLC27A4). The pharmaceutical composition can be formulated in acid- resistant (enteric-release) dosage forms for oral administration in patients. This disclosure is further directed to a process for producing the LCFA-conjugated bioactive agent including protein, polypeptide, small molecule drugs, DNA, RNA, oligonucleotide, or a combination thereof (abstract).
Roloff et al. teach: The present disclosure generally provides nucleotide-based compounds useful for treating various diseases, including cancer. In some aspects, the disclosure provides oligonucleotides that are chemically modified to include an engineered fatty-acid residue, for example, to assist with improving the half-life of such compounds or assisting with cell penetration (e.g., penetration into tumor cells). In some aspects, the disclosure provides compositions that include such modified nucleotides and a protein, such as albumin or mimetics thereof. The disclosure provides various uses of the compounds and compositions (abstract)(page 7) (instant claims 1, 20, 21, and 24). The oligonucleotide meets the instant limitation of being a variant of an aptamer.
The structure taught in the abstract is:
PNG
media_image1.png
148
346
media_image1.png
Greyscale
Roloff et al. teach incorporation of NH-CO (pages 2, 13, and 21) (instant claim 7), carboxyl groups (pages 2, 14, and 21) (instant claim 2), an ethylene glycol group (pages 17 and 21), siRNAs (pages 19 and 20), miRNAs (page 20), compounds HB1-HB16 (pages 20-21), compounds HA1-HA4 (pages 21 and 22)(instant claims 18 and 30), pharmaceutical preparations (page 22)(instant claim 24), and ODDA-conjugated siRNAs (page 30) (instant claims 20 and 21).
Roloff et al. teaches that the nucleic acid to be conjugated is a siRNAs, miRNA, or antisense sequence (claim 8). Roloff et al. teach incorporation of a PEG group or ethylene glycol units (instant claims 4 and 6). Roloff et al. teaches incorporation of a glutamic acid group (instant claim 10).
It would have been obvious to incorporate any of the structural elements of Roloff et al. into the conjugate of Shen because each are directed to delivery of nucleic acid molecules. One would have reasonably expected for the structural elements taught by each to be combinable and to benefit in the delivery of the nucleic acids taught by Shen and Roloff et al.
Suckow et al. teach conjugates for nucleic acid delivery for half-life extension. The conjugate can comprise a piperazine group (instant claims 14 and 15), carboxyl groups [0084], linear fatty acid, and NH-CO amide group [0014] (claims 10 and 11).
Suckow et al.t each that the oligonucleotide conjugate comprise4s a nucleic acid selected from antisense oligonucleotides, small interfering RNA (siRNA), microRNA mimics, short hairpin RNAs (shRNA), single-strand small interfering RNA (ssRNAi), RNaseH oligonucleotides, anti- microRNA oligonucleotides, steric blocking oligonucleotides, exon-skipping oligonucleotides, CRISPR guide RNAs, and aptamers. [0099](claim 155).
PNG
media_image2.png
120
558
media_image2.png
Greyscale
It would have been obvious to incorporate any of the structural elements of Suckow et al. into the conjugate of Shen because each are directed to delivery of nucleic acid molecules. One would have reasonably expected for the structural elements taught by each to be combinable and to benefit in the delivery of the nucleic acids taught by Shen and Roloff et al. It would have been obvious for the oligonucleotide to be an aptamer because Suckow et al. is evidence that aptamers are delivered via the same conjugates taught for siRNA and antisense delivery.
Grinstaff et al. teach a DBCO-PEG3-glutamic acid-valine-citrulline-p-aminobenzylcarbamate-MMAE (DBCO-MMAE) molecule formulated by piperidine chemistry and linked to a therapeutic aptamer for delivery. Grinstaff et al. is additional evidence of known structural elements for delivery of therapeutic agents.
Each of GTFA-1, 2, and 3 are conjugates composed of well-known building blocks, as collectively taught by the cited references (PEG linkers, amide bonds, azide groups, glutamate/glutamic acid derived moiety, and a long-chain dicarboxylic acid fragment). The structures are considered to be a result of design choice by combining structural elements known to benefit specific nucleic acid delivery (instant claims 19 and 27). Additionally, Suckow et al. teaches the structure of GTFA-1’ (Figure 1N).
The claims are not directed to any specific conjugate that has demonstrated an unexpected result with a specific nucleic acid, but rather are directed to an enormous possible genus of conjugate structures with varying combinations of structural elements that are obvious in view of the prior art.
It would have been obvious to incorporate the aptamer of instant SEQ ID NO: 1 or any aptamer with a known therapeutic effect with expectation of successful delivery. The aptamer of instant SEQ ID NO: 1 was known, as taught by Zhu et al.(Table 1, SEQ ID NO: 3, VFW aptamer) (instant claims 35 and 36).
Zhu et al. teach: The present disclosure relates to agents, compositions targeting to von Willebrand factor (VWF). The VWF targeting agents are synthetic polynucleotides, including VWF binding agents and their reversal agents. The VWF binding agents are VWF binding aptamers that bind to and inhibit the VWF activities (abstract).
Zhu et al. teach that the aptamer is modified with a conjugate including a PEG polymer and fatty acid [0030].
Zhu et al. teach: [0132] As used herein, the term “fatty acid” refers to a carboxylic acid (or organic acid), often with a long aliphatic tail, either saturated or unsaturated. Generally, fatty acids have a carbon-carbon bonded chain of at least 8 carbon atoms in length, more preferably at least 12 carbons in length. Most naturally occurring fatty acids have an even number of carbon atoms because their biosynthesis involves acetate which has two carbon atoms. The fatty acids may be in a free state (non-esterified) or in an esterified form such as part of a triglyceride, diacylglyceride, monoacylglyceride, acyl-CoA (thio-ester) bound or other bound form.
Zhu et al. teach: [0133] In some embodiments, the VWF binding agents described herein may be conjugated to a saturated fatty acid. As used herein, the term “saturated fatty acids” do not contain any double bonds along the chain. In some embodiments, the saturated fatty acids do not contain any other functional groups along the chain. In some embodiments, the saturated fatty acids contain other functional groups along the chain. The term “saturated” refers to hydrogen, in that all carbons (apart from the carboxylic acid [ — COOH] group) contain as many hydrogens as satisfied by valency.
Zhu et al. teach that the fatty acid can be palmitic acid [0136] (instant claim 36).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
Prosecution Insights