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 .
Status of Claims
Claims 2-7, 11, 13, 16-17, 20, 30, 38, 43, 45, 49-50,54, 56, 77, 84-85, 124, and 135 are pending.
Priority
Claims 2-7, 11, 13, 16-17, 20, 30, 38, 43, 45, 49-50,54, 56, 77, 84-85, 124, and 135 are a 371 of PCT/US 2022/022006 filed on March 25, 2022, which has priority to PRO 63/220,271 filed on July 9, 2021, and to PRO 63/166,119 filed on March 25, 2021.
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, 11, 20, 30, 45, 54, 85 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 “5’-X1AUCUX2UX3-3’, wherein X1, X2, and X3 are independently selected from A, C, U or G”. However, this limitation for the nucleotide sequence is recited twice. It is unclear whether multiple distinct sequences were intended or whether the repetition is in error. Because of this, a person of ordinary skill would not be able to ascertain the metes and bounds of the claim language. Additionally, the specification at paragraph [0011] also recites the duplicate limitation.
Regarding claim 11, the phrase "e.g. GGGGS" 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 20 recites “comprises or consists of the amino acid sequence”. The use of “comprise or consist of” renders the claim indefinite because “comprise” is an open-ended term while “consist of” is a closed-ended term excluding unrecited elements or steps. Given this, it is unclear whether the claim encompasses additional unrecited elements or is limited to only the recited elements.
Claim 30 “comprises or consists of the amino acid sequence”. The use of “comprise or consist of” renders the claim indefinite because “comprise” is an open-ended term while “consist of” is a closed-ended term excluding unrecited elements or steps. Given this, it is unclear whether the claim encompasses additional unrecited elements or is limited to only the recited elements.
Regarding claim 45, the phrase "(e.g., N-1-mehtyl-pseudouridine)" 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 54, the phrase "e.g., about 50-70 nm" 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 54, the phrase "e.g., 10% (w/v) trehalose in water, or sucrose, e.g., 10% (w/v) sucrose in water" 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 54 recites “(w/v)” in line 14. The use of parentheses “()” in the claim is interpreted as providing exemplary information rather than limiting the claim scope. As such, the claim language is rendered indefinite.
Regarding claim 85, the phrase "e.g., a beta-coronavirus, e.g., SARS-CoV-2" 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 § 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.
Claims 2-7, 11, 13, 16-17, 38, 43, 45, 49-50, 54,56, 77, 84-85, 124, and 135 are rejected under 35 U.S.C. §103 as being unpatentable over Hassert et al. [mRNA induced expression of human angiotensin-converting enzyme 2 in mice for the study of the adaptive immune response to severe acute respiratory syndrome coronavirus 2, PLoS Pathog., 2020], in view of Claude Carrier et al. (Hereinafter Carrier) [Trans-acting effectors versus RNA cis-elements: a tightly knit regulatory mesh, Front. Microbiol., 2020], in view of Trepotec et al. [Maximizing the translational yield of mRNA therapeutics by minimizing 5’-UTRs, Tissue Engineering Part A: Research Advances, 2018], in view of Gao et la. [Delineation of the exact transcription termination signal for type 3 polymerase III, Molecular Therapy: Nucleic Acids, 2018], in view of Lei et al. [Neutralization of SARS-CoV-2 spike psuedotyped virus by recombinant ACE2-Ig, Nature Communications, 2020], in view of Siriwattananon et al. (Hereinafter Siri) [Development of plant-produced recombinant ACE2-Fc fusion protein as a potential therapeutic agent against SARS-CoV-2, Front Plant Sci, January 2021], in view of Glasgow et al. [Engineered ACE2 receptor traps potently neutralize SARS-CoV-2, Biophysics and computational biology, 2020], in view of Chakraborty et al. [US 9107886 B2, 2015], in view of
For claim 2, Hassert et al. teaches an mRNA optimized nucleotide sequence that includes an extracellular domain of a human angiotensin-converting enzyme 2 (hACE2) [Author Summary ¶ 1]. However, Hassert et al. does not teach coding regions of optimized sequences consisting of codons associated with a usage frequency greater than or equal to 10% and where the optimized nucleotide sequence does not contain a termination signal, does not contain any negative cis-regulatory elements and negative elements, has a codon adaptation index greater than 0.8 when the optimized nucleotide sequences are divided into non-overlapping 30 nucleotide-long portions with a guanine/cytosine content.
For this limitation, Carrier et al teaches that cis-acting RNA sequence motifs and structural elements regulate mRNA translation, stability, and overall transcript fate, and that these elements interact with regulatory factors capable of influencing gene expression [Abstract]. Additionally, Trepotec et al. discloses optimization of mRNA constructs through selection and modification of untranslated region sequences improve translation efficiency by reducing inhibitory sequence, e.g. negative cis-regulatory and negative repeat elements, features and secondary structures [Abstract]. Given this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Hassert et al. that discloses an optimized mRNA expressing hACE2 with the additional teachings of both Carrier et al. and Trepotec et al. by eliminating sequence motifs, repetitive elements, and other cis-acting features known to negatively affect mRNA stability or translation. Based on this, there is a reasonable expectation of success that a person of ordinary skill would combine the teachings of Hassert et al. with the teachings of Carrier et al. and Trepotec et al. for the purpose of optimizing a mRNA expressing hACE2 where the optimized mRNA lacks negative cis-regulatory elements and negative repeat elements leading to greater stability and translation.
For claim 3 where the optimized nucleotide sequence does not contain a termination signal with certain sequences, Gao et al. teaches that termination efficiency and actual termination depend on a T-stretch signal where the T-stretch is greater than or equal to 6 [Abstract]. Here, a person of ordinary skill would recognize that a T-stretch of 6 or more would translate to a U-stretch of 6 or more in RNA, and given that it functions as a termination motif, it would have been prima facie obvious to a person of ordinary skill in the art to exclude such sequences during optimization of the hACE2-encoding nucleotide sequence.
For claim 4 where the extracellular domain of the hACE2 protein comprises amino acid residues 1-740 of a naturally occurring hACE2 protein encoded by SEQ ID NO: 10, Hassert et al. the expression of the naturally occurring hACE2 protein which necessarily includes the amino acid residues 1-740 corresponding to its extracellular domain [Author Summary ¶ 1]. Therefore, Hassert et al. discloses a polypeptide comprising amino acid residues 1-740 of the naturally occurring hACE2 protein.
For claim 5 where the polypeptide comprises two extracellular domains of hACE2 protein and is operably linked to a dimer, Lei et al. teaches that a recombinant fusion protein made up of the extracellular domains of hACE2 linked to the Fc region of human IgG1 [Methods: Generation of fusion proteins]. Lei et al. further demonstrates that Fc-mediated dimerization produces stable bivalent hACE2 constructs capable of binding to SARS-CoV-2 spike proteins [Abstract].
For claims 6 and 7 where the IgG1 derived Fc region is linked to the extracellular domain of the hACE2 protein, Lei et al. further discloses that the human IgG1 Fc is located on the C-terminus [Fig. 1].
For claim 8 where the extracellular domain of the hACE2, the C-terminal localization sequence, or the Fc region are linked by a linker sequence, Siri teaches that the hACE2, with a GenBank accession number NP 001358344.1, was designed to join with the Fc region of human IgG1 using a peptide linker such as GGGGS [Materials and Methods: Plasmid Construction for Expression of ACE2-Fc]. Here, it would have been prima facie obvious prior to the filing of the claimed invention to modify the systems and methods of Hassert et al. that discloses an optimized hACE2 polypeptide with the additional teachings of Lei et al. and Siri where a Fc region of IgG1 is joined by a peptide linker, e.g. GGGGS, at the C-terminus. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art creating a fusion protein using hACE2 combined with a Fc region like human IgG1 would use a peptide linker on the C-terminus.
For claim 13 where one or more amino acid substitutions increase binding affinity of the human ACE2 protein for SARS-CoV-2 spike protein and/or inactivate the catalytic activity of hACE2 protein, Glasgow et al. demonstrated that enrichment for ACE2 variants with mutations at the N90 glycosylation site, and histidines in positions 374 and 378 together coordinate the necessary Zn ion enzymatic activity [Results ¶ 5]. Furthermore, the amino acid substitutions at 374 and 378 abolish catalytic activity and improve binding affinity per Applicant’s specification at [¶ 103].
For claims 16 and 17 where the one or more amino acid substitutions are selected from N90D and R273A, N90D and T92A, or H374N and H378N, Glasgow et al. teaches amino acid substitutions at H374N and H378N [Results ¶ 6].
For claim 38 where the tail structure of the mRNA comprises a poly(A) tail or a poly(C) tail, Hassert et al. teaches a hACE2 mRNA construct with a 153 base adenosine nucleotide stretch as a polyA tail [Results: hACE2 mRNA construct].
For claim 43 a 5’ untranslated region different than the naturally occurring 5’ UTR of hACE2, Hassert et al. discloses the use of a beta globin 5’ UTR for optimization of mRNA expression in mammalian cells. Hassert et al. also discloses the use of a 3’ UTR from alpha globin for mRNA stability [Id.].
For claim 45 where one or more modified nulceosides is a nucleoside analog that includes inosine, Chakraborty et al. teaches the use of inosine as a nucleoside analog as a 5’ terminal cap [Para starting with “According to the present invention, 5’ terminal caps”]. Furthermore, nucleoside analogs, including inosine, are well-known RNA modifications used to alter RNA properties such as stability and immune recognition. Given this, there is a reasonable expectation of success that a person of ordinary skill would combine the teachings of Hassert et al. with the further teachings of Lei et al. and Chakraborty et al. for a polypeptide that comprises a modified hACE2 with substitutions at H374N and H378N combined with a known nucleoside analog such as inosine to further stabilize the mRNA construct and improve binding affinity to the spike glycoprotein of SARS-CoV-2.
For claim 49 where the mRNA is used in a therapy, both Hassert et al. and Chakraborty et al. disclose the purpose of the optimized mRNA construct is therapeutic in nature [Introduction ¶ 1 and Para starting with “Notwithstanding these reports which are limited to a selection”].
For claim 50 where a DNA vector encoding a mRNA, Hassert et al. teaches the use of pUC57 vector backbone made up of four components: a type II T7 promoter for a high transcription rate in vitro, a beta globin 5” UTR, a 3’ UTR alpha globin for mRNA stability, and a 153 base adenosine nucleotide stretch as the polyA tail [Results: hACE2 mRNA construct ¶ 1].
Additionally, for claim 54 where a lipid nanoparticle encapsulates the mRNA, Chakraborty et al. discloses the use of lipid nanoparticles, e.g. liposomes, where the mRNA is encapsulated or it can be contained in an aqueous core which can then be encapsulated by the liposome [Para starting with “In one embodiment, pharmaceutical compositions may include liposomes”].
For claim 56, Chakraborty et al. states the cationic lipids can be selected from any one of international publication numbers that include No. WO2012040185, etc., where the publication references novel cationic lipids can be used in combination with other lipid components such as cholesterol and PEG lipids to form lipid nanoparticles [Background of the invention].
For claims 77 and 84 where the composition of claim 54 may be a pharmaceutical composition, Chakraborty et al. teaches compositions that include pharmaceutical compositions [Para starting with “Described herein are compositions (including pharmaceutical compositions)”]. Furthermore, Hassert et al., and several of the other cited references, are directed towards developing a method of treatment for SARS-CoV-2 [Abstract]. Additionally, Chakraborty et al. discloses that the invention is related to compositions, methods, processes, kits, and devices [Field of the Invention, Summary of the invention]. Given this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Hassert et al. that is related to an optimized mRNA construct encoding a hACE2 protein with the teachings of Chakraborty et al. that discloses the use of modified mRNAs for the purpose of developing pharmaceutical compositions and/or kits for therapeutic and scientific use.
For claim 85 where a method of treating or preventing an infection in a subject caused by a virus, Hassert et al., along with Lei et al., are directed to treating or preventing, e.g. neutralization, of SARS-CoV-2 [Abstract, respectively].
For claim 124 where administration involves intravenous or by nebulization, Chakraborty et al. discloses a pharmaceutical composition containing a modified mRNA can be administered via various means to include intravenous injection, as well as other routes [Para starting with “While these lipidoids have been used to effectively”].
For claim 135 where a dry powder formulation comprising spray-dried particles comprising lipid nanoparticles, Chakraborty et al. states the compositions may also be formulated for direct delivery to an organ or tissue in any of several ways in the art including gels, powders, ointments, creams, gels, lotions, etc. [Para starting with “The compositions may also be formulated for direct delivery”]. Given this, there is a reasonable expectation of success that a person of ordinary skill in the art would combine the teachings of Hassert et al. that disclosed an optimized mRNA construct directed at treating and/or neutralizing SARS-CoV-2 with the additional teachings of Chakraborty et al. that discusses modified mRNA constructs being administered for therapeutic purposes as pharmaceutical compositions that include intravenous routes and/or nebulization but can also include dry powder formulations that comprise spray-dried particles of the therapeutic composition that includes lipid nanoparticles. Given this, it would have been prima facie obvious to a person of ordinary skill in the art prior to the filing of the claimed invention to modify the systems and methods of Hassert et al. with the additional teachings of Chakraborty to develop an optimized mRNA construct that included specific amino acid substitutions along with other components that are known to increase efficacy and stabilization in mRNA constructs in order to develop a pharmaceutical composition containing a modified mRNA construct for treating viral infections.
The Supreme court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable varition..103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions…
…the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) emphasis added.
In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton.").
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN DAVID MOORE whose telephone number is (703)756-1887. The examiner can normally be reached M-F 8-5.
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, Tracy Vivlemore can be reached on 571-272-2914. 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.
/JOHN DAVID MOORE/Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights