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 172-183 and 186-191 are currently pending in this application.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 172-189, in the reply filed on Oct. 23, 2025 is acknowledged. Applicant’s election of the species of Oct4 circular RNA comprising SEQ ID NO: 33 and the Oct4 having SEQ ID NO: 1 is acknowledged. Claims 190-191 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 172-183 and 186-189 have been considered on the merits.
Previous Rejections
Status of the rejections: the previous claim rejections under 112(a)-WD, 112(b) and 112(d) are withdrawn in view of the claim amendments except as maintained below.
Claim Interpretation
In the claims, the term “contacting” is interpreted under a broadest reasonable interpretation as encompassing contacting a cell with a single RNA molecule or plurality of identical RNA molecules (e.g., coincubation) as well as transfecting, electroporating, into the cell a single RNA molecule or a DNA encoding and expressing a recombinant circular RNA (see e.g., instant [0045], [0132], [0141], [0143]-[0144]).
In claim 172, the phrase “contacting the somatic cell with at least one circular RNA encodes” the factors of (a), (b), (c) or (d)” is interpreted as encompassing contacting the cell with a single copy or multiple copies of a single circular RNA encoding all the recited factors as well as a single or plurality of copies of different circular RNAs encoding different factors, and/or different subcombinations of factors, so long as at least one circular RNA encoding each required factor is contacted to the cell. Similarly, in claim 182 the phrase “contacting the somatic cell with at least 2, at least 3, at least 4, at least 5, or at least 6 circular RNAs” encompasses contacting with six copies of the same circular RNA or six different circular RNAs as well as intermediate permutations wherein each circular RNA may comprise one, some, or all of the sequences encoding Oct4, Sox2, Klf4, C-Myc, L-Myc, Lin28, and/or Nanog.
In claim 174, the phrase “has the sequence of” with regard to a reprogramming factor and a recited SEQ ID NO. is interpreted as meaning the protein “consists” of a polypeptide with the recited sequence.
For claims 180-181, the lipid nanoparticle (LNP) complex is interpreted in view of [0083] to encompass any lipid molecule conjugated to a circular RNA wherein the lipid molecule is less than a micron in size, such as conjugation via a covalent bond, electrostatic adsorption, or a biotin-streptavidin interaction.
Claim Rejections - 35 USC § 112(a), New Matter (new)
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.
Claim 177 is 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 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 with an RNA comprising an N-6-methyladenosine (m6A) residue. This lacks support in the application as filed and thus constitutes new matter.
37 CFR 1.118(a) states “No amendment shall introduce new matter into the disclosure of an application after the filing date of the application”. In the instant case, the recitation of the limitation “N-6-methyladenosine (m6A) residues” (Claim 177) is considered new matter. Upon review of the instant specification, examiner could not find explicit or implicit support for this limitation in the instant filing or in any priority document. Rather, the specification seems to define “m6A” as an abbreviation for “M-6-methyladenosine” ([0125] or original claim 17) while being silent as to any “N-6-methyladenosine” residue or RNA of the invention comprising such.
Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of the method of instant claim 177.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph-written description requirement”. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981) teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed…If a claim is amended to include subject matter, limitation or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.06 further notes, “When an amendment is filed in reply to an objection or rejection based on U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendment made to the disclosure”.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
Claim Rejections - 35 USC § 112(a) - Written Description, (modified)
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.
Claim 172-183, 186, and 188-189 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 claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claim 172 is directed to methods comprising maintaining a fibroblast or CD34+ cell contacted with at least one circular RNA encoding an Oct4, Sox2, Klf4, Lin28, and a recited Myc paralog such that an induced pluripotent stem cell (iPSC) is produced. However in view of claim 186, claim 172 encompasses wherein the cell is either in suspension or is not in suspension during the maintaining and contacting. Thus, the scope of claim 172 encompasses somatic cells that are CD34+ and maintained in adherent conditions under which iPSC is obtained. Similarly, the scope of claim 172 encompasses somatic cells that are fibroblasts maintained in suspension conditions under which iPSC is obtained. None of the dependent claims narrow this scope except for claim 187.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to describe a single method of converting CD34+ cells to iPSC without adherent conditions or of converting a fibroblast into iPSC using any suspension condition. Instead the working examples show fibroblasts under adherent culture conditions (Examples 5-6) and CD34+ cells under suspension conditions (Examples 7-8). Furthermore, the description constantly describes the CD34+ cell as in suspension or suspension culture or as a “suspension cell.”
The prior art teaches reprogramming adherent fibroblasts into iPSCs via RNAs encoding Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc) (Warren2 (Warren and Lin, Mol Ther 27(4): 729-34 (2019) at pg. 731, left col.). The prior art also teaches reprogramming CD34+ cells by induced expression of Yamanaka factors (Khazaei et al., Front Cell Dev Biol 4:152 (2017) at Fig. 1, pg. 4, left col., last para., to right col., 1st para.). However the prior art is silent as to such methods comprising suspension culture of fibroblasts or adherent culture of CD34+ cells.
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the scope methods for fibroblast and CD34+ cells wherein the method comprises (1) fibroblasts in suspension conditions throughout the method or (2) CD34+ cells that never experience a suspension condition during the method. Nothing in dependent claims 173-183, 186, and 188-191 cures this deficiency.
Response to Arguments
Applicant's remarks filed 6/4/26 regarding the previous 112(a)-WD rejections (pg. 6) have been fully considered and found persuasive except regarding the lipid nanoparticle (LNP) aspect. Moreover, applicant’s claim amendments resulted in new grounds of rejection laid out above.
The lack of written description rejection above is supported by the remarks at pg. 10-11 of the response regarding the complexity and unpredictability of using circRNA for protein expression and reprogramming technologies generally, e.g.. unique and difficult-to-control parameters: “expression of protein using circRNA is highly unpredictable and depends on many factors . . .” including general RNA turnover rate and/or endonuclease activity, sequence specific translation inhibition and/or degradation, and the presence/absence of RNA stabilizing proteins (citing Wesselhoeft and Carey et al., Cell Stem Cell 9: 588-98 (2011)). “It is also known in the art that reprogramming is a highly unpredictable technology with many variables that may affect outcome.” (pg. 11).
35 USC § 112(a), Scope of Enablement (modified)
Claims 172-183 and 186-189 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable any person, skilled in the art to which it pertains or with which it is most nearly connected to, to produce a reprogrammed iPSC merely by any contacting of a fibroblast or CD34+ cell with a circular RNA(s) encoding the specifically recited gene products of claim 172.
Although the vast majority of methods encompassed by the instant claims lack enablement, it is noted that there are enabled embodiments wherein the contacting comprises some means of introducing the RNA into the interior of the cell, i.e., to pass through the plasma membrane or be synthesized within the cell (e.g., transfection or transduction), and wherein each contacting comprises a multitude of circular RNA molecules and provides for sustained expression of the encoded products (whether continuous or noncontinuous) over a period of about at least 6 days (which may require repeated contacting events depending on the half-life of the circular RNA(s) introduced within the cell). All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of claims 172-183 and 186-189:
The claims are directed to a method of producing an induced pluripotent stem cell (iPSC) whereby the method comprises (1) contacting a somatic cell with one or more recombinant circular RNA as recited in the claims and, then, (2) maintaining the cell under conditions to achieve said producing. The claims are broad in that the contacting of the somatic cell with the RNA encompasses any type of contacting without limitation (see e.g., instant [0141]-[0144], [0170], [0199]).
Further in view of claims 180 or 181, all the claims encompass methods of producing an iPSC wherein the method comprises contacting the somatic cell with one or more recombinant circular RNA conjugated with an LNP to form a complex wherein the RNA is as recited in the claims (e.g., claim 172). The term lipid nanoparticle (LNP) complex encompass any lipid molecule conjugated to a circular RNA wherein the lipid molecule is less than a micron in size, such as conjugation via a covalent bond, electrostatic adsorption, or a biotin-streptavidin based on instant [0083]. Thus, the claims are broad in that the complex may consist of a single lipid conjugated to a single circular RNA so long as the lipid is less than 1 micron in size but not requiring the RNA to be encapsulated by any lipid structure. The term “lipid” encompass millions of species including very small lipids, such as fatty acids like ethanoic acid or propionic acid and phosphoinositides, like diacylglycerol comprising the aforementioned, as well as waxes (e.g., cetyl palmitate) (see e.g., Asokapandian et al., Lipids and oils: an overview. 2021 Feb 11:389-411 at pg. 389-392).
The state of the art:
As made previously of record, the prior art teaches RNA generally, or naked circular RNA, is not stable in extracellular environments and is not readily absorbed into cells without more direct interventions, such as chemical disruption of membranes, electroporating, transfecting and/or targeting with protective lipid nanoparticles encapsulating the RNA. For example, the prior art teaches specific RNA-based reprogramming of human somatic cells to iPSCs requires RNA transfection or viral infection (Preskey et al., at pg. 746, left col., last para.; Warren et al., Cell Stem Cell 7: 18-30 (2010), IDS ref.; Yoshioka et al., Cell Stem Cell 13: 246-54 (2013); Sarkar et al., Nat Commun 11: 1545 (2020)). The prior art also teaches the expression of reprogramming factors via RNA-based methods can take at least up to 10 days (Annand, R., Methods Mol Biol 2239: 163-74 (2021)).
Thus, these aspects of using must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue or unreasonable burden on such artisan: (1) using mere contacting of the somatic cell with the circular RNA is sufficient to transport sufficient RNA inside the cell to result in expression of the factors required; and (2) mere complexes of nanolipid and circular RNA can deliver and express the RNA in the cell.
The amount of direction and guidance as well as any working examples provided:
The instant specification notes that the term “contacting” may encompass transfecting a circular RNA (circRNA), or a vector comprising a nucleic acid (e.g., a DNA molecule) encoding the same, into the cell, such as using lipid-mediated transfection, Lipofectamine®, and/or other transfection reagents ([0141]). The instant application notes that the contacting can be performed multiple times, which is also known in the art. The instant specification notes prophetically that circRNA-LNP complexes can be introduced into cells by merely contacting with the cells in the absence of any transfection reagent ([0294]).
The instant specification provides working examples using transfecting of circRNA or circRNA-LNP complexes according to a ThermoFisher® Lipofectamine® RNAiMax commercial product’s instructions, Neon® nucleofection electroporation system, or DOTAP liposomal transfection technique (Examples 3-9). Furthermore, all the working examples rely on repeating daily transfections for at least 4-6 days.
Nowhere does the instant specification show how to reprogram a somatic cell into an iPSC by a single contacting with a single recombinant circular RNA molecule. Instead, 25,000-75,000 cells were transfected with 30 ng circular RNA according to Lipofectamine® manufacturer’s instructions. This is equivalent to about 0.5-1 pg per cell, or tens of thousands of RNA molecules per cell per transfection. Therefore, in all the working examples at least a subset of the cells are contacted thousands of times by thousands of RNA molecules (and LNP complexes thereof) in a single transfection event. Similarly, at least a subset of the cells are contacted at least dozens or hundreds of times by copies of the same circular RNA.
Thus, there is no evidence in the instant application or the prior art that the scope of contacting encompassed by the claims could predictably result in reprogramming a somatic cell into an iPSC by performing the methods as recited in the claims. Rather, the evidence is limited to specific contacting techniques comprising repeated transfection over 4-6 days.
Undue experimentation would be required to fill these gaps and unpredictability. Undue experimentation is required to reprogram a somatic cell using only a single contacting with a single circular RNA or whereby the RNA does not enter the cell’s interior but merely contacts an outer surface, such as wherein the RNA is complex with a small lipid to form the LNP (i.e., any lipid less than 1 micron in size).
In summary, the claims are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement to a person skilled in the art to which it pertains or with which it is most nearly connected to produce an iPSC via merely contacting the cell with the circular RNA(s) as recited in the claims. Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims, undue and/or unreasonable experimentation would have been required for one skilled in the art to produce the recited product over the full scope of the methods of claims 172-183, 186, and 188-189.
Response to Arguments
Applicant's remarks filed 6/4/26 regarding the previous enablement rejections (pg. 6-7) have been fully considered and found persuasive (regarding somatic cell type and required reprogramming factors) except as maintained above. Moreover, applicant’s claim amendments resulted in the new grounds of rejection laid out above.
The lack of enablement rejection above is supported by the remarks at pg. 10-11 of the response regarding the complexity and unpredictability of using circRNA for protein expression and reprogramming technologies generally, e.g.. unique and difficult-to-control parameters: “expression of protein using circRNA is highly unpredictable and depends on many factors . . .” including general RNA turnover rate and/or endonuclease activity, sequence specific translation inhibition and/or degradation, and the presence/absence of RNA stabilizing proteins (citing Wesselhoeft and Carey (2011)). “It is also known in the art that reprogramming is a highly unpredictable technology with many variables that may affect outcome.” (pg. 11).
Claim Rejections - 35 USC § 112(b)
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 180-181 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.
In claims 180-181, the term lipid nanoparticle (LNP) is used to mean any lipid-based particle in the submicron size range, including non-bilayer structures ([0083]). However, the ordinary meaning of “lipid nanoparticle” means a spherical, ellipsoid, or rod-shaped micelle or bicelle-like structure due to the assembly of amphipathic lipids in a polar solvent. If the applicant acts as her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). In the instant case, there is no such redefinition, and, thus, the term “lipid nanoparticle (LNP)” as used in the claims is indefinite.
Response to Arguments
Applicant's arguments filed 6/4/26 regarding the previous 112(b) rejections have been fully considered and found persuasive except regarding the scope of lipid nanoparticle or LNP. This term is not defined in the claims or application and thus takes its ordinary and customary meaning in the art under a broadest reasonable interpretation. In view of instant [0083], the terms “lipid nanoparticle” and “LNP” describe lipid-based particles in the submicron range and may not have the structural characteristics of liposomes nor any bilayer structure. Thus a lipid nanoparticle is encompasses any lipid below the maximum size requirement. Nothing in [0123] sets forth any limiting definition, instead this paragraph merely provides non-limiting examples of lipids.
Claim Rejections - 35 USC § 112(d), (maintained)
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.
Claim 189 is 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 189 further recites only language regarding a result(s) of the claimed method without any further active step implying, by the logic of the claims as drafted, that the method as recited in claim 172 inherently produces these results. Thus, this dependent claim fails to further limit the subject matter of claim 172.
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, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments
Applicant's arguments filed 6/4/26 regarding the 112(d) rejections have been fully considered and found persuasive except regarding the scope of claim 189. Based on the logic of the claims as drafted, performing the method of claim 172 either results as described in claim 189 or it does not. As claim 189 adds no additional step or feature to claim 172, then either claim 172 inherently satisfies the limitations of claim 189 or claim 189 lacks sufficient detail to show definiteness, possession, and/or enablement. For now, the Office has made a prima facie case for the former in the art rejections, but the potential for 112 rejections of claim 189 in the future are noted for applicant’s consideration before responding. This 112(d) rejection is akin to a claim dependence formality and can be remedied by canceling claim 189, incorporating the limitations of claim 189 into claim 172, or rewriting claim 189 as an independent claim. In essence, Applicant is being requested to preemptively resolve the issue by deciding whether claim 172 inherently produces the result(s) recited in claim 189 or confirm the missing feature (lack of inherency) to ensure such results occur, e.g., by amending claim 189 to contain an additional step or limitation to the method of claim 172 as actively performed.
This issue is based on the applicant’s own framing of the invention in the claim structure (i.e., claim dependency and wording) as dependent claim 189 implies the recited results are not ensured to occur merely by satisfying all limitations of claim 172 and by the principle of claim differentiation implying claim 189 is missing an essential step or feature. Furthermore, within claim 189 the delineating of different results with “and/or” implies only one or less than all of the recited results occurs by performing the method of claim 172. Again implying lack of essential steps or features regarding every individual result recited. Applicant is being afforded consideration of these issues in case these implications were not intended and are just an unintentional artefact of claim drafting, especially in light of interrelated issues/rejections (e.g., 112(a) issues and interpreting teachings in the prior art in view of the principle of inherency).
Claim Rejections - 35 USC § 102, (maintained)
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 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.
Claims 172-174, 176, 178, 186, and 189 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stadtfeld (US 20160326497 A1).
Regarding claim 172, Stadtfeld discloses a method comprising contacting a somatic fibroblast cell (introducing into (e.g., using transduction or transfection) with an exogenous circular RNA(s) encoding the exogenous reprogramming factors Oct4, Klf4, Sox2, and myc (e.g., c-Myc) as well as Lin28 and/or Nanog and culturing the contacted fibroblast in a medium for an amount of time sufficient to generate iPSCs, e.g., 3-8 days or about 9 days ([0007]-[0011], [0013], [0018], [0050], [0087], [0115], [0121]).
Regarding claim 173, Stadtfeld discloses wherein the first four reprogramming factors are specifically human ones and the Nanog may be a human Nanog ([0011]).
Regarding claim 174, Stadtfeld discloses wherein the Oct4 has a sequence (SEQ ID NO: 2) identical to instant SEQ ID NO: 1, as show below.
Query Match 100.0%; Score 1948; Length 361;
Matches 360; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAGHLASDFAFSPPPGGGGDGPGGPEPGWVDPRTWLSFQGPPGGPGIGPGVGPGSEVWGI 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MAGHLASDFAFSPPPGGGGDGPGGPEPGWVDPRTWLSFQGPPGGPGIGPGVGPGSEVWGI 60
Qy 61 PPCPPPYEFCGGMAYCGPQVGVGLVPQGGLETSQPEGEAGVGVESNSDGASPEPCTVTPG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PPCPPPYEFCGGMAYCGPQVGVGLVPQGGLETSQPEGEAGVGVESNSDGASPEPCTVTPG 120
Qy 121 AVKLEKEKLEQNPEESQDIKALQKELEQFAKLLKQKRITLGYTQADVGLTLGVLFGKVFS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 AVKLEKEKLEQNPEESQDIKALQKELEQFAKLLKQKRITLGYTQADVGLTLGVLFGKVFS 180
Qy 181 QTTICRFEALQLSFKNMCKLRPLLQKWVEEADNNENLQEICKAETLVQARKRKRTSIENR 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QTTICRFEALQLSFKNMCKLRPLLQKWVEEADNNENLQEICKAETLVQARKRKRTSIENR 240
Qy 241 VRGNLENLFLQCPKPTLQQISHIAQQLGLEKDVVRVWFCNRRQKGKRSSSDYAQREDFEA 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 VRGNLENLFLQCPKPTLQQISHIAQQLGLEKDVVRVWFCNRRQKGKRSSSDYAQREDFEA 300
Qy 301 AGSPFSGGPVSFPLAPGPHFGTPGYGSPHFTALYSSVPFPEGEAFPPVSVTTLGSPMHSN 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 AGSPFSGGPVSFPLAPGPHFGTPGYGSPHFTALYSSVPFPEGEAFPPVSVTTLGSPMHSN 360
Regarding claim 176, Stadtfeld anticipates wherein the circular RNA is substantially non-immunogenic by virtue of anticipating claim 172 as set forth fully above because there are no structural feature(s) recited or implied by the language of claim 176, and because circular RNAs are inherently less immunogenic than linear RNAs with regard to inducing the expression and/or activity of an interferon-regulated gene(s).
Regarding claim 178, as shown above Stadtfeld discloses wherein the RNA encodes Oct4 having the sequence according to instant SEQ ID NO: 1, which is inherently larger than 200 nucleotides and further must be over 1080 nucleotides to provide expression of the Oct4.
Regarding claim 186, Stadtfeld discloses wherein the cell (MEF) is adherent or in suspension (Example I).
Regarding claim 189, Stadtfeld discloses the same active method steps as required by claim 189 as set forth fully above regarding claim 172 because there is no additional step or feature implied in claim 189.
Thus, Stadtfeld anticipates the claimed invention.
Response to Arguments
Applicant's remarks filed 6/4/26 regarding the 102 rejections (pg. 8-9) have been fully considered but not found persuasive. Applicant argues that Stadtfeld does not teach a circular RNA outside of a general definition of “nucleic acid” and that Stadtfeld lacks enablement.
As noted by the response, Stadtfeld at [0050] as cited in the rejection does state the “nucleic acid” can be an RNA in linear or circular form (pg. 9, lines 1-2). As Stadtfeld discloses at least at [0009] exposure of a somatic cell to exogenous reprogramming factors via introduction of an exogenous “nucleic acid” encoding the reprogramming factors into the at least one somatic cell, e.g., introduced via viral transduction or transfection, Stadtfeld clearly discloses using RNAs in a “circular form” for reprogramming a somatic cell as means of expressing reprogramming factors, e.g., Oct4, Klf4, Sox2, Myc proteins, Nanog, and Lin28 ([0011]).
Applicant argues despite what is disclosed in Stadtfeld, it’s total disclosure in view of the prior art is not enabling for actually making a fibroblast or CD34+ cell into an iPSC, e.g., by transfection of such circular RNA(s) into the cell and maintaining the cell under conditions until this occurs. Note, when a reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. “Once such a reference is found, the burden is on applicant to rebut the presumption of operability.” MPEP 2121. Applicant sole argument here is no disclosure of any working embodiment in Stadtfeld; however, this argument alone is insufficient to overcome the prima facie case of enablement in prophetic descriptions in Stadtfeld.
A finding of anticipation “does not require the actual creation or reduction to practice of the prior art subject matter; anticipation requires only an enabling disclosure.” Schering Corp. v. Geneva Pharms., 339 F.3d 1373, 1380 (Fed. Cir. 2003). A prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, (Fed. Cir. 2006) (citing Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1326, (Fed. Cir. 2005)).
This is a question of undue experimentation as Stadtfeld provides all the required elements of claim 172. A prior art reference is not necessarily inadequate just because it leaves the skilled artist to engage in some measure of adaptation or testing as a specification may call for a reasonable amount of experimentation to make and use an invention. Amgen Inc. v. Sanofi, 598 U.S. 594, 611-612 (2023). As of the earliest effective filing date of Stadtfeld, methods of forced expression of just four of the required factors was already known to convert a fibroblast into an iPSC, methods of transfecting RNAs into a fibroblast were already known and established for achieving reprogramming factor expression, and circular RNAs were known in the prior art (Warren at pg. 621-624; Yoshioka at abstract; Pasman et al., RNA Biol. 14: 975-7 (2016) at abstract). Thus, the combination of Stadtfeld in view of its prior art at May 6, 2016 provide enabling disclosure of the method of claim 172. It is noted that claim 172 recites the claimed method only at a high level of generality (e.g., no specific condition(s) or amount/duration/dosage of expression of any encoded factor(s) to ensure robust and sustained expression suggesting these are not essential).
Claim Rejections - 35 USC § 103, (modified)
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.
Claims 172-174, 176-179, 186, and 189 are rejected under 35 U.S.C. 103 as being unpatentable over Stadtfeld in view of Yang (Yang et al., Cell Res 27: 626-41 (2017)).
The claims are interpreted as set forth in a previous section. As set forth above, Stadtfeld anticipates claims 172-174, 176, 178, 186, and 189, and thus, Stadtfeld renders obvious the subject matter of claims 172-174, 176, 178, 186, and 189.
Regarding claim 177, Stadtfeld does not teach wherein the circular RNA comprises one or more N-6-methyladenosine (m6A) residues.
However Yang teaches incorporating m6A residues promotes translation of circular RNAs (Abstract; Fig. 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to make the circular RNA used in the method taught by Stadtfeld such that it incorporates m6A nucleotides. One of ordinary skill in the art with the goal of achieving strong expression of the reprogramming factors in a human cell would be motivated by Yang teaching improved expression for circular RNAs comprising m6A nucleotides.
Regarding claim 179, Stadtfeld does not teach wherein the circular RNA comprises an IRES operably linked to the coding sequence.
However Yang teaches using an IRES in a circular RNA to provide protein expression (Fig. 1; pg. 626, right col.) and that m6A nucleotides function as an IRES (pg. 627, left col., last para., Fig. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to make the circular RNA used in the method taught by Stadtfeld to have an IRES in front of the reprogramming factor coding sequence(s). One of ordinary skill in the art with the goal of achieving strong expression of the reprogramming factors would be motivated by Yang teaching constructs engineered with various IRES sequences all successful drove protein expression from circular formats.
Claims 172-174, 176, 178, 180-181, 186, and 189 are rejected under 35 U.S.C. 103 as being unpatentable over Stadtfeld in view of Wesselhoeft (Wesselhoeft et al., Molecular Cell 74(3): 508-20 (2019); IDS ref.).
As set forth above, Stadtfeld anticipates claims 172-174, 176, 178, 186, and 189, and thus, Stadtfeld renders obvious the subject matter of claims 172-174, 176, 178, 186, and 189.
Regarding claims 180-181, Stadtfeld does not teach wherein the circular RNA is complexed with a lipid nanoparticle (LNP), either covalently or non-covalently.
However Wesselhoeft teaches wherein expression vectors consisting of circular RNAs are encapsulated into lipid nanoparticles for deliver to target cells (pg. 515, left col., last para., to pg. 516, left col., 2nd para.)
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to contact the circular RNA in the method taught by Stadtfeld using an LNP delivery system taught by Wesselhoeft that non-covalently complexes circular RNA to LNP. One of ordinary skill in the art would be motivated by Wesselhoeft teaching LNP delivery was equivalent to electroporation but provides an advantage for being less immunogenic than linear RNAs (unrecognized by cellular RNA sensors), such as for in vivo use or with TLR-competent somatic cells (Abstract; pg. 515, left col., last para., to pg. 516, left col., 2nd para.; Fig. 4-6).
Claims 172-174, 176, 178, 182, 186, and 188-189 are rejected under 35 U.S.C. 103 as being unpatentable over Stadtfeld (US 20160326497 A1) in view of Warren (Warren et al., Cell Stem Cell 7: 18-30 (2010), IDS ref.).
As set forth above, Stadtfeld anticipates claims 172-174, 176, 178, 186, and 189, and thus, Stadtfeld renders obvious the subject matter of claims 172-174, 176, 178, 186, and 189.
Regarding claim 182, Stadtfeld does not expressly teach wherein the cell is contacted with at least 4 circular RNAs encoding the reprogramming factor(s).
However Warren teaches RNA-based methods of iPSC generation comprising daily consecutive transfections of different RNAs together encoding four different reprogramming factors, one RNA type per reprogramming factor (Fig. 2; pg. 621, left col., last para., to pg. 624, left col., 1st para.).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to perform the method taught by Stadtfeld using a different circular RNA per exogenous reprogramming factor (i.e., Oct4, Klf4, Sox2, and C-Myc) such that the cell is transfected with 4 circular RNAs in view of Warren. One of ordinary skill in the art would be motivated by Warren teaching RNA-based methods of iPSC generation comprising transfections of 4 different RNAs, one per reprogramming factor. Note, an overlapping range between the prior art and a claim provides a prima facie case of obviousness (see MPEP 2144.05).
Regarding claim 188, as set forth above for claim 182, Warren teaches wherein a combination of different RNAs (one per reprogramming factor) are repeatedly transfected at least 4 times (pg. 623, left col., 1st para.). Note, an overlapping range between the prior art and a claim provides a prima facie case of obviousness (see MPEP 2144.05).
Claims 172-174, 176, 178, 182-183, 186, and 188-189 are rejected under 35 U.S.C. 103 as being unpatentable over Stadtfeld and Warren as applied above, and further in view of Wang2 (Wang et al., Biol Open 8: bio047225 (2019)).
Regarding claim 183, although Stadtfeld and Warren does not expressly teach wherein the cell is contacted with exactly 5 or 6 circular RNAs encoding the recited reprogramming factors; Stadtfeld teaches further including exogenous nucleic acids encoding Nanog and/or Lin28 ([0008]-[0011]) and Wang2 teaches the combination of Oct4, Klf4, Sox2, c-Myc and Lin28 or the combination of Oct4, Klf4, Sox2, c-Myc, Lin28 and Nanog more efficiently reprograms iPSCs (e.g., 76-fold) than using the four factors OSKM alone (Abstract; Fig. 1; pg. 2 left col., 3rd para., to right col., 1st para.; Fig. 4B; pg. 8, left col., last para, to right col.). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to perform the method taught by Stadtfeld and Wang2 using 6 or 7 circular RNAs, with one per factor respectively encoding Oct4, Klf4, Sox2, C-Myc and Lin28, or Oct4, Klf4, Sox2, C-Myc, Lin28 and Nanog. One of ordinary skill in the art would be motivated by Wang2 teaching the beneficial synergistic effect on increasing reprogramming efficiency.
Claims 172-174, 176, 178, 186-187, and 189 are rejected under 35 U.S.C. 103 as being unpatentable over Stadtfeld in view of Ye (Ye et al., Blood 114: 5473-80 (2009)) and ThermoFisher (StemPro™-34 medium and CD34+ cell kit, gibco user guide, ThermoFisher Scientific (2020)).
As set forth above, Stadtfeld anticipates claims 172-174, 176, 178, 186, and 189, and thus, Stadtfeld renders obvious the subject matter of claims 172-174, 176, 178, 186, and 189.
Regarding claim 187, Stadtfeld does not teach wherein the somatic cell is a CD34+ cell in suspension. However Ye teaches reprogramming adult CD34+ cells from patient samples into iPSCs using forced expression of Oct4, Sox2, Klf4, and c-Myc from a viral vector in order to study hematopoiesis and hematological cancers (abstract; pg. 5474, left col., 3rd para.). ThermoFisher teaches culturing and maintaining in suspension commercially available human CD34+ cells derived from blood, such as in a commercially available medium for hematopoietic progenitor cells, including during reprogramming into induced pluripotent cells (iPS) (pg. 2, right col., Day -3: Seed cells).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select the somatic cell for the method of Stadtfeld that is a CD34+ as taught by Ye for studying hematopoiesis and/or blood cancers and to expand/maintain the CD34+ cell in suspension as taught by ThermoFisher. One of ordinary skill in the art with the goal of studying cancer would be motivated to avoid using viral vectors in their study to avoid confounding transformation events and, thus, would use a non-viral vector alternatives like a circular RNA transfection method taught by Stadtfeld.
Response to Arguments
Applicant's remarks filed 6/4/26 regarding the previous 103 rejections (pg. 10-14) have been fully considered but not found persuasive. Applicant argues both a lack of motivation to combine the references and a reasonable expectation of success.
As noted above, Stadtfeld discloses using RNAs in a “circular form” for reprogramming a somatic cell as means of expressing reprogramming factors, e.g., Oct4, Klf4, Sox2, Myc proteins, Nanog, and Lin28 ([0011]), such as in a fibroblast ([0013]) via RNA introduction via transfection ([0011]-[0013]).
As the basis of the 103 rejections rests on the anticipation of the base claim 172 by Stadtfeld, there is no requirement for a motivation to combine references in order to find claims 172-174, 176, 178, 186, and 189 obvious over Stadtfeld.
Regarding expectations of success, Applicant argues the prior art has found the art of stem cell reprogramming to be a highly unpredictable technology with many variables that may affect the outcome and more specific art references emphasize expression of protein using circRNA is highly unpredictable and depends on many factors, including general RNA turnover rate or endonuclease activity, sequence-specific translation inhibition or degradation, and the presence or absence of RNA stabilizing proteins (Wesselhoeft at page 518, right col'n, 3rd paragraph). Applicant points out the same authors state that "more work needs to be done to fully investigate the potential of circRNA for therapeutic and non-therapeutic applications, including further optimizations of protein translation from circRNA, citing Wesselhoeft 2 at page 7, left col'n, 1st paragraph. Applicant argues the complexity and unpredictability of protein expression using circRNA and that of the reprogramming technology generally, and the lack of any enabling disclosure in the cited references, one skilled in the art would not have reasonably expected to reach the method of reprogramming a fibroblast or a CD34+ cell into iPSCs by contacting the cells with circular RNAs as presently claimed merely based on the teachings of Stadtfeld.
However it is noted that the reasonable expectation of success in the rejection above is for a “minimal” success and not requiring anything beyond that, e.g., regarding optimization or efficiency. The prior art provides numerous examples of reprogramming somatic cells, most commonly fibroblasts, into iPSC using expression of the same reprogramming factors albeit from a DNA vector or mRNA and that efficiencies vary, with higher efficiency not always preferable (Buganim at pg. 305). The prior art also provides numerous examples of forced ectopic expression from introduced RNAs encoding products of interest, such as to avoid permanent genetic engineering (see e.g., Schott et al., Mol Ther 24: 1513-27 (2016) at abstract, Table 1). Thus, the skilled worker has enough guidance to achieve success at least in some circumstances aiming for a results-effective variable of low efficiency iPSC production, such as the variable of sufficient factors expression to achieve iPSC generation, and allowing for the skilled worker to engage in some reasonable amount of adaptation, experimentation and testing (e.g., to achieve sufficient expression levels and stoichiometry of the necessary reprogramming factors based on the RNA form utilized).
Although not framed explicitly as such, the response (pg. 11, 2nd para.) appears to argue evidence of advantageous unexpected results overcome even a prima facie case of obviousness: “the present application demonstrates remarkable technical effects of reprogramming fibroblasts and CD34+ cells with circRNA encoding reprogram factors, including, e.g., increased reprogramming efficiency, accelerated MET kinetics, lower toxicity during early reprogramming, generation of more iPSClike colonies at earlier timepoints, and quicker colony maturation” (see, e.g., Specification at [0336], [0340]). However the claims lack any limitation regarding efficiency, speed, and/or toxicity
Regarding dependent claims 180-183, and 187-188, Applicant also argues due to the complexity and unpredictability of protein expression using circRNA and reprogramming technology, the lack of suggestion to combine Stadtfeld with any other cited references, and the lack of any enabling disclosure in the cited references, one skilled in the art would not have reasonably expected to reach the method of reprogramming a fibroblast or a CD34+ cell into iPSCs by contacting the cells with circular RNAs as presently claimed merely based on the teachings of the cited references.
As discussed above, a reasonable expectation of success is found for Stadtfeld in view of the prior art of its filing date. The motivations to combine Stadtfeld with other references above only bolster the reasonable expectation of success by utilizing prior art features for known prior art purposes to improve factor expression (e.g., levels and durations). Namely, Yang teaching improved expression for circular RNAs comprising m6A nucleotides, a motivation to achieving strong expression of the reprogramming factors in a human cell would motivated this RNA modification, further improving upon the reasonable expectation of success. Furthermore, (1) Warren’s established RNA-based methods of iPSC generation comprising transfections of 4 different RNAs, one per reprogramming factor or (2) Wang2’s established method using precisely 6-7 different nucleic acids, with one per factor, providing beneficial synergistic effect on reprogramming would each allow for some individualized expression levels and stochiometric expression optimization, if desired. Moreover, the use Wesselhoeft teachings of encapsulated RNAs into lipid nanoparticles for delivery to target cells to avoid/reduce immunological issues, such as for TLR-competent fibroblast or CD34+ somatic cells.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 172-179, 182-183, and 186-189 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 25, 38, 50, 52-53, 55, 57, 77, 80, 93, 97, 103, 110-111, 116, 137, 142, 144-145, and 150 of copending Application No. 18/745761 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1 and 4 of the reference application teaches a method of producing an induced pluripotent stem cell (iPSC) from a blood cell and/or CD34+ cell in suspension whereby the method comprises contacting the cell with one or more circular RNAs encoding at least one of Oct3/4, Klf4, Sox2, Nanog, Lin28, c-Myc, and L-Myc; and maintaining the cell under conditions under which a reprogrammed iPSC is obtained. Furthermore, reference claims 52-53, 142, 144-145, and 150 requires performing such a method to obtain an iPSC, and reference claims 110-111, 116, and 137 disclose an intermediate product of such a method.
Regarding instant claim 173 and 176-179, reference claim 5 teaches wherein the factor is a human or humanized factor (a), is non-immunogenic (p), comprises one or more M-6-methyladenosine residues (q), comprises from about 200-5000 nucleotides (r), or comprises an IRES operably linked to the protein coding sequence (s).
Regarding instant claims 174-175, reference claims 5 and 57 each teaches the method wherein the Oct3/4 has the amino acid sequence (SEQ ID NO: 7) of instant SEQ ID NO: 1 as shown below.
100.0% identity in 360 residues overlap; Score: 1948.0; Gap frequency: 0.0%
SEQ ID 1 1 MAGHLASDFAFSPPPGGGGDGPGGPEPGWVDPRTWLSFQGPPGGPGIGPGVGPGSEVWGI
Sequence7 1 MAGHLASDFAFSPPPGGGGDGPGGPEPGWVDPRTWLSFQGPPGGPGIGPGVGPGSEVWGI
************************************************************
SEQ ID 1 61 PPCPPPYEFCGGMAYCGPQVGVGLVPQGGLETSQPEGEAGVGVESNSDGASPEPCTVTPG
Sequence7 61 PPCPPPYEFCGGMAYCGPQVGVGLVPQGGLETSQPEGEAGVGVESNSDGASPEPCTVTPG
************************************************************
SEQ ID 1 121 AVKLEKEKLEQNPEESQDIKALQKELEQFAKLLKQKRITLGYTQADVGLTLGVLFGKVFS
Sequence7 121 AVKLEKEKLEQNPEESQDIKALQKELEQFAKLLKQKRITLGYTQADVGLTLGVLFGKVFS
************************************************************
SEQ ID 1 181 QTTICRFEALQLSFKNMCKLRPLLQKWVEEADNNENLQEICKAETLVQARKRKRTSIENR
Sequence7 181 QTTICRFEALQLSFKNMCKLRPLLQKWVEEADNNENLQEICKAETLVQARKRKRTSIENR
************************************************************
SEQ ID 1 241 VRGNLENLFLQCPKPTLQQISHIAQQLGLEKDVVRVWFCNRRQKGKRSSSDYAQREDFEA
Sequence7 241 VRGNLENLFLQCPKPTLQQISHIAQQLGLEKDVVRVWFCNRRQKGKRSSSDYAQREDFEA
************************************************************
SEQ ID 1 301 AGSPFSGGPVSFPLAPGPHFGTPGYGSPHFTALYSSVPFPEGEAFPPVSVTTLGSPMHSN
Sequence7 301 AGSPFSGGPVSFPLAPGPHFGTPGYGSPHFTALYSSVPFPEGEAFPPVSVTTLGSPMHSN
************************************************************
Regarding instant claim 182-183, reference claim 25 teaches wherein the contacting comprises six separate circular RNAs encoding the six factors.
Regarding instant claims 185-187, reference claims 1 and 4 teach wherein the cell is CD34+ and/or in suspension.
Regarding instant claim 188, reference claim 38 teaches wherein the cell is contacted with a circular RNA multiple times, including 2-4 times or more than 2, 3, or 4 times.
Regarding instant claim 189, reference claim 50 teaches whereby the method results in more reprogrammed iPSCs than using linear RNA(s) and/or a decrease in toxicity compared to using linear RNA(s).
This is a provisional nonstatutory double patenting rejection because the reference application claims have not in fact been patented.
Claims 172-183 and 186-189 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 25, 38, 50, 52-53, 55, 57, 77, 80, 93, 97, 103, 110-111, 116, 137, 142, 144-145, and 150 of copending Application No. 18/745761 (reference application) in view of Wesselhoeft (Wesselhoeft et al., Molecular Cell 74(3): 508-20 (2019); IDS ref.).
Although the reference claims do not teach wherein the circular RNA is complexed with a lipid nanoparticle (LNP), either covalently or non-covalently, it was known in the prior art to use LNPs for RNA delivery to a cell. Wesselhoeft teaches wherein expression vectors consisting of circular RNAs are encapsulated into lipid nanoparticles for deliver to target cells (pg. 515, left col., last para., to pg. 516, left col., 2nd para.). Thus, it would have been prima facie obvious to one of ordinary skill in the art to contact the circular RNA(s) in the methods of the reference claims using an LNP delivery system taught by Wesselhoeft that non-covalently complexes circular RNA to LNP. One of ordinary skill in the art would be motivated by Wesselhoeft teaching LNP delivery was equivalent to electroporation but provides an advantage for use in vivo for being less immunogenic but provides an advantage for being less immunogenic than linear RNAs (unrecognized by cellular RNA sensors) for use or with TLR-competent blood cells (Abstract; pg. 515, left col., last para., to pg. 516, left col., 2nd para.; Fig. 4). This is a provisional nonstatutory double patenting rejection because the reference application claims have not in fact been patented.
Response to Remarks
The response is consider nonresponsive as double-patenting rejections will not be held in until pending claims are allowable. See 37 C.F.R. 1.111(b), which allows that some objections or “requirements as to form” may be held in abeyance but includes no provision for holding rejections in abeyance. Section 1.111(b) also requires applicants to respond to each rejection with “arguments pointing out the specific distinctions believed to render the claims, including any newly presented claims, patentable over any applied references.” For each rejection, for example, applicants might provide a proper terminal disclaimer (or at least indicate a willingness to submit one when double patenting is the only remaining issue); explain why the rejection is overcome by amendments; provide convincing arguments that the rejection was made in error; and/or explain why amendments or claim cancellations in the copending applications have rendered the rejection moot. If any of the conflicting pending application matures to a patent, modifying the rejection to account for claim-number changes will not constitute a new ground of rejection.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
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