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 .
Application Status
This action is written in response to applicant’s correspondence received 02/28/2024. Claims 1-5, 7, 28-31, 34, 37-38, 43-44, 47, 49, 64, 96-97 are currently pending.
Priority
This application is a CON of PCT/US2022/017067 filed on 02/18/2022. Acknowledgment is made of applicant's claim for priority based on US Provisional Applications 63/151,337, filed on 02/19/2021 and 63/195,518, filed on 06/01/2021.
Claim Objections
Claim 1 is objected to for:
1) reciting “the SHM enzyme” without defining that it is the same term as the recited “an enzyme capable of mediating SHM”;
2) Using “An” instead of “A” before “nucleic acid”.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 49 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 49 is rejected under 35 USC §101 because the claimed invention is directed to non-statutory subject matter. The term "cell" as defined by the specification at page 79 ¶[0322] lines 3-5 stating that “and/or an engineered cell (e.g., an engineered immune cell) expressing the recombinant antigen-binding molecule as described herein to a subject in need thereof”. Since a human egg or human embryo is encompassed by the term "cell", the cell is present or intended to be present in a human being, said cell becoming integrated into the human being and therefore being an inseparable part of the human itself. The scope of the claim, therefore, encompasses a human being, which is non-statutory subject matter.
As such, the recitation of the limitation "non-human" would be remedial. See 1077 O.G. 24, April 21, 1987.35.
Claims 1-5, 28-31, 34, 37-38, 43-44, 49 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., law of nature, natural phenomenon, or product of nature) without significantly more. The inventor discloses and claims naturally occurring nucleic acid constructs or cells. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Regarding claims 1-5, 28-31, 34, 37-38, 43-44, 49, see the subject matter eligibility test below:
Step 1:
The claims 1-5, 28-31, 34, 37-38, 43-44, 49 recite "nucleic acid construct”, “composition”, “vector”, or “engineered cell”. Thus, the claimed inventions are directed to a process, machine, manufacturer or composition of matter.
Step 2A, Prong 1:
Claim 1 recites a “nucleic acid construct comprising a) a third nucleic acid sequence encoding an antigen-binding molecule of interest, and b) a nucleic acid sequence encoding an enzyme capable of mediating SHM, wherein the coding sequence for the SHM enzyme is operably linked to an inducible promoter, wherein the inducible promoter is induced by an immune response”. Thus, claim 1 refers to a judicial exception because the recited limitations encompass naturally occurring human chromosomes (hChrs), e.g. hChr 22, and others that comprise a naturally occurring a nucleic acid sequence encoding an antigen-binding molecule, such as IGL (See NCBI Gene ID: 3535 profile in NPL listed on PTO-892; Info provided by RefSeq, Jul 2008), which is a gene that encodes the lambda light chain of immunoglobulins, such as IgG, IgM, along with IgA, IgD, and IgE, as all immunoglobulin classes are composed of two heavy chains and either two kappa or two lambda light chains; hChr 22 also comprises the well-studied enzyme capable of mediating SHM, APOBEC3B (A3B, See NCBI Gene ID: 9582 profile in NPL listed on PTO-892; Info provided by RefSeq, Jul 2012), which has a NF-𝛋B binding sites in its promoter region taught by Maruyama et al. (Classical NF-κB pathway is responsible for APOBEC3B expression in cancer cells. Biochem Biophys Res Commun. 2016 Sep 23;478(3):1466-71; Hereinafter, Maruyama; Abstract, lines 8), therefore, it is operably linked to an inducible promoter by immune responses (taught by the instant claim 3). The claimed nucleic acids are products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 2 recites “…the inducible promoter is selected from the group consisting of a nuclear factor kappa-B (NF-𝛋B) promoter…”, this claim encompasses human chromosomes such as hChr22 (see analysis above for claim 1). Thus, claim 2 refers to a judicial exception because it recites products of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claim 3 recites “ … wherein the SHM enzyme is selected from the group consisting of … APOBEC3B … this claim encompasses human chromosomes, such as hChr22 (see analysis above for claim 1). Thus, this claim refers to a judicial exception because it recites product of nature that lack any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Regarding claim 4, since an antigen-binding molecule-encoding gene, such as IGL on hChr22 is non-heterologous, thus, this claim refers to judicial exception that lacks any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Regarding claim 5, since an antigen-binding molecule-encoding gene, such as IGL on hChr 22 is operatively linked to a promoter, taught by Staudt et al., (Immunoglobulin gene transcription. Annu Rev Immunol. 1991;9:373-98; Hereinafter, Staudt; Pages 375 & 377; Figures 1 & 2), this claim refers to judicial exception that lacks any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Regarding claim 28, the recitation “wherein the antigen-binding molecule comprises an immune receptor, an immunoglobulin, and an antibody or a functional fragment thereof” encompasses human chromosomes encoding all of the recited gene products that has antigen-binding characteristics, e.g. immunoglobulin lambda light chain (IGL, See NCBI Gene ID: 3535 profile in NPL listed on PTO-892) and the SHM enzyme APOBEC3B (A3B, See NCBI Gene ID: 9582 profile in NPL listed on PTO-892; Info provided by RefSeq on July 2012) on the human chromosome 22. Thus, this claim is a judicial exception because the claimed nucleic acid constructs are products of nature that lack of any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Regarding claim 29, the recitation of “immunoglobulin” encompasses human chromosomes encoding immunoglobulins, such as hChr22. Thus, this claim is a judicial exception due to lack of any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Regarding claim 30, the recitation “wherein the immunoglobulin is selected from the group consisting of IgA, IgD, IgE,IgG, and IgM” encompasses human chromosomes encoding immunoglobulins, such as hChr22, because all classes of immunoglobulins could include the lambda light chain. Thus, this claim is a judicial exception due to lack of any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Regarding claim 31, the recitation “wherein the antigen-binding molecule comprises an immune receptor, an immunoglobulin, and an antibody or a functional fragment thereof” encompasses human chromosomes encoding immunoglobulins, such as hChr22, because lambda light chain is a fragment of immunoglobulins. Thus, this claim is a judicial exception due to lack of any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Regarding claim 34, the recitation “…an immunoglobulin superfamily member…” encompasses human chromosomes encoding immunoglobulins, such as hChr22, because lambda light chain is an immunoglobulin. Thus, this claim is a judicial exception due to lack of any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claims 36-37 recite ”… nucleic acid sequence encoding the antigen-binding molecule is configured as a single chain comprising a first segment encoding a first variable region and a second segment encoding a second variable region” or “nucleic acid sequence comprises a linker that operably links the first segment and the second segment”, and both claims encompass human chromosomes encoding immunoglobulins, such as hChr22, because lambda light chain is an immunoglobulin that comprises the recited features, e.g. the IGL locus contains numerous functional Vλ variable segments, joining Jλ segments, and constant Cλ segments as taught by Das et al. (Evolutionary redefinition of immunoglobulin light chain isotypes in tetrapods using molecular markers, Proc. Natl. Acad. Sci. U.S.A. 105 (43) 16647-16652; Published 10/28/2008; Page 16647, left column 3rd ¶). Thus, these claims are judicial exceptions due to lack of any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claims 43-44, 47 recite “A composition comprising a plurality of the nucleic acid constructs of claim 1” or “A vector comprising the nucleic acid construct of claim 1” or “A composition comprising a plurality of the vectors of claim 44”, and all 3 claims encompass human chromosomes encoding immunoglobulins, such as hChr12 and hChr 22 because there are a plurality of similar nucleic acid constructs or vectors like hChr12 or hChr22 in a human cell or isolated from a human cell. Thus, these claims are judicial exceptions due to lack of any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Regarding claim 49, the recitation “an engineered cell comprising the nucleic acid construct of claim 1” encompasses naturally occurring human B cells or T cells. Thus, this claim is a judicial exception due to lack of any markedly different structural or functional characteristics as compared to its closest naturally occurring counterpart.
Claims 7, 64, 96-97 pass the subject matter eligibility test because the limitations of these claims are interpreted as imparting markedly different structural or functional characteristics as compared to its closest naturally occurring expression system. Therefore, these claims are NOT directed to judicial invention.
Step 2A, Prong 2:
Claims 1-5, 28-31, 34, 37-38, 43-44, 49 do NOT recite any additional elements, and therefore, they do not include or recite additional elements that integrate the judicial exception into a practical application.
Step 2B:
Claims 1-5, 28-31, 34, 37-38, 43-44, 49 do NOT recite any additional elements, and therefore, they do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
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 1-5, 28-31, 34, 37-38, 43-44, 49, 64, 96-97 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.
Where applicant acts as his or 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). The claim term “third” in claims 1, 4-5, 37-38 is redefined in the specification to mean “… merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.” (Instant specification, page 20, ¶[0121], lines 4-6) while the accepted meaning is “third in multiple…” The term is indefinite because the specification does not clearly redefine the term despite reciting “Use of ordinal terms such as "first", "second", "third", etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another” in specification (page 20, ¶[0121], lines 1-3). However, the re-definition does not define the context normally associated with the term “third”, i.e. the recitation of “third” implies there is “first” and “second” even if there is no more “priority”, “precedence”, or “order” associated with the elements. One with ordinary skill in the art would not be appraised of the metes of bounds of the claims reciting this redefined term because the definition in specification does not clarify whether there are additional elements having a same name (but for use of the ordinal term) as missing limitations, which makes the claims indefinite. In contrast, claim 7 recites “first”, “second”, and “third” with the appearance of the accepted meaning of “third” which further reinforces the confusion that there might be missing elements in the rejected claims above despite the redefined meaning in specification.
Claims 2-3, 28-31, 34, 49, 64, 96-97 are also rejected for depending from the rejected claim 1 and failing to remedy the indefiniteness therein.
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 4 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. The recitation that “wherein the third nucleic acid is heterologous or non-heterologous” does not further limit the nucleic acid construct of claim 1 because there isn’t a third category of nucleic acid that is neither “heterologous” nor “non-heterologous” in the same context.
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.
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.
Claims 1-5, 28-31, 43-44, 47, 49, 64, 96-97 are rejected under 35 U.S.C. 103 as being unpatentable over Saulquin et al. (WO2020148206, published 07/23/2020; Included in IDS filed on 08/05/2024; Hereinafter, Saulquin) in view of Rydzek et al. (Chimeric Antigen Receptor Library Screening Using a Novel NF-κB/NFAT Reporter Cell Platform. Mol Ther. 2019 Feb 6;27(2):287-299; Hereinafter, Rydzek), in further view of Shaimardanova et al. (Production and Application of Multicistronic Constructs for Various Human Disease Therapies. Pharmaceutics. 2019 Nov 6;11(11):580; Hereinafter, Shaimardanova).
Saulquin (2020) teaches a method for in vitro affinity maturation of antibodies (Page 2, Abstract, line 8) that uses a population of B cells or eukaryotic cells engineered for expressing an antibody (i.e. an antigen-binding molecule; Page 52, claim 3) to express a “gene editing platform that consists of … a non-nuclease DNA modifying enzyme…” (Page 52, claim 5), “wherein the DNA modifying enzyme derives from the Activation Induced cytidine Deaminase (AID)” (Page 52, claim 9). The instant application teaches that AID is one of the embodiments of the SHM enzymes (claim 3).
However, Saulquin does not teach a nucleic acid encoding a SHM enzyme operably linked to an inducible promoter, wherein the inducible promoter is induced by an immune response.
Rydzek (2019) teaches “a platform that enables rapid and high-throughput CAR-screening campaigns with reporter cells … equipped with nuclear factor kB (NFκB) …reporter genes that generate a duplex output of enhanced CFP (ECFP) and EGFP, respectively. As a proof of concept, we modified reporter cells with CD19-specific and ROR1-specific CARs, and we detected high-level reporter signals that allowed distinguishing functional from non-functional CAR constructs” (Abstract, lines 4-14), wherein CAR refers to chimeric antigen receptor, which is an antigen-binding molecule well known in the art. And the NF-κB response element promoter was taught by Rydzek in the screening assay to drive the reporter gene expression in response to the binding characteristic differences of the antigen-binding molecule when interacting with the antigen of interest (see nucleic acid construct schematic shown in Figure. 2A (Page 289) and Figure. 3A (Page 291), shown below.
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Figure 2A. Figure 3A.
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Regarding claim 1, the instant specification teaches that “a” and “an” includes plural references (Page 15, ¶[0104]). Despite that FIG. 10 of the instant specification shows drawings of a single circular nucleic acid construct with plural expression cassettes, the broadest reasonable interpretation (BRI) of the claim in few of the definitions in the specification includes embodiments that multiple nucleic acid constructs comprise the claimed elements, i.e. a) a nucleic acid sequence encoding an antigen-binding molecule of interest, and b) a nucleic acid sequence encoding an enzyme capable of mediating SHM, wherein the coding sequence for the SHM enzyme is operably linked to an inducible promoter, wherein the inducible promoter is induced by an immune response.
However, neither Saulquin nor Rydzek teaches integrative expression construct with multiple gene expression system on a single nucleic acid construct.
Saulquin does not explicitly teach that both the nucleic acid used to engineer cells for expressing an antibody, i.e. and antigen-binding molecule, and the aforementioned AID are parts of “an nucleic acid construct”.
Shaimardanova (2019) teaches that “The safety and effectiveness of the joint delivery of therapeutic genes in multicistronic vectors based on the internal ribosome entry site (IRES) and self-cleaving 2A peptides have been shown in both in vitro and in vivo experiments as well as in clinical trials” (Abstract, lines 6-8) and outlines the benefits of multicistronic nucleic acid constructs in the review of the state of art (Page 4/16, Table 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the separate nucleic acid constructs described by Saulquin by incorporating the knowledge of an immune response-inducible, i.e. a synthetic inducible promotor containing NF-κB response elements driven gene expression system described by Rydzek to activate AID expression, to drive SHM triggered by antigen binding and arrive at the same invention as claimed, with the teachings, suggestions, and motivations provided by Saulquin and Rydzek to create an in vitro simulation system for SHM-based affinity maturation of antibodies in B cells. Whether the nucleic acid construct is composed as a single multicistronic expression construct or multiple distinct nucleic acid constructs is a matter of routine laboratory optimization by one with ordinary skill in the art based on the teachings of the instant application in view of the teachings of Shaimardanova.
Regarding claim 2, Rydzek teaches that the activation of AID expression can be controlled by direct binding of NF-𝛋B to the AID promoter (Page 287, Abstract, lines 7-8).
Regarding claim 3, Saulquin teaches that the SHM enzyme in the nucleic acid construct is AID (Page 1, Abstract, line 1; FIG. 2A).
Regarding claim 4, nucleic acid constructs expressed in HEK293 cells are either heterologous or non-heterologous.
Regarding claim 5, Saulquin further teaches “In some embodiments, the construct further includes regulatory sequences. A "regulatory sequence" includes promoters, enhancers, and other expression control elements…” (Page 27, lines 14-16).
Regarding claim 28 & 31, Saulquin further teaches that the antigen-binding molecule is an antibody (Page 2, claim 2).
Regarding claim 29, Saulquin further teaches that the term "antibody" or "immunoglobulin" have the same meaning (Page 6, line 7).
Regarding claim 30, Saulquin further teaches that “The specificity and avidity of IgG expressing HEK 293 cells was analysed by flow cytometry” (Page 38, line 31-32).
Regarding claim 43, Saulquin further teaches “Examples of additional components of the kits include, but are not limited to, one or more host cells, one or more reagents for introducing foreign nucleotide sequences into host cells, …” (Page 34, lines 24-26). “Kits” is interpreted the same as “compositions” as there is no practical difference between the two terms.
Regarding claim 44, Saulquin further teaches that “HEK 293 cells were engineered to express cell surface A2Ab by stable transfection of episomal vectors expressing its heavy and light chains (HC and LC, respectively). For induction of mutations, these cells were then transiently transfected with a plasmid coding for AID*Δ fused to MS2 coat protein…” (Page 42, lines 7-11). Also, the instant specification teaches that “a” and “an” includes plural references (Page 15, ¶[0104]), so “a vector” in claim 44 can be interpreted to include embodiments where multiple vectors are used, and again, it’s a matter of routine laboratory optimization for one with ordinary skill in the art.
Regarding claim 47, Saulquin further teaches a composition comprising a plurality of vectors such that “This invention further provides kits containing reagents for performing the above-described methods, including …, and nucleic acid molecules …, the non-nuclease DNA modifying enzyme, …, a nucleic acid molecule encoding for the non-nuclease DNA modifying enzyme, … a plurality of multimers as disclosed herein … for the binding protein so as to perform the affinity-based selection…” (Page 34, lines 10-20).
Regarding claim 49, Saulquin further teaches “The population of cells …that can express the binding protein preferably at the cell surface.” (Page 16, lines 33-34). And that “The mutagenesis consists of contacting the population of cells engineered for expressing the binding protein …, a non-nuclease DNA modifying enzyme …” (Page 17, lines 18-23).
Regarding claim 64, Saulquin further discloses “The first object of the present invention relates to a method of generating and selecting a variant of a binding protein with increased binding affinity and/or specificity that consists of subjecting a population of cells that express the binding protein to at least one round of mutagenesis coupled to an affinity/specificity-based selection and immunomagnetic enrichment.” (Page 17, lines 27-30), wherein “The affinity/specificity-based cell selection and immune magnetic enrichment starts with … contacting … population of cells with a plurality of multimers made up by mixing specific and unspecific target molecules for the binding protein” (Page 28, lines 20-22; Claim 18, page 53).
Regarding claim 96, Saulquin further teaches detailed steps of “purifying and/or producing the antigen-binding molecule from the identified single engineered cell expressing the antigen-binding molecule thereof” claimed in the current application by detailing “Antibody sequence evolution during mutagenesis and selection rounds” on pages 43 line 12-page 44 line 12, and teaching the steps of “Characterization of evolved antibodies against HLA-A2” on page 44 lines 13-19 by reciting “The R2+ antibodies C4.4 and C4.18 … were produced as recombinant proteins for comparison of their affinity and specificity to those of the initial A2Ab... This is an almost two log increase over that of the initial A2Ab”.
Regarding claim 97, this is a product-by-process claim. In view of the specification regarding the claimed product: “In certain embodiments, the altered affinity is a higher affinity. In some embodiments, the altered affinity is due to an alteration in association constant. In other embodiments, the altered affinity is due to an alteration in dissociation constant. In other embodiments, the altered affinity is due to an alteration in specificity for the target antigen” (Page 11, ¶[0066]), under the broadest reasonable interpretation (BRI), the shared core characteristic of the product-by-process is “altered affinity”.
Saulquin further teaches that “Starting from a low affinity monoclonal antibody expressed on Ag-specific naive blood circulating B cells, they obtained in approximately 6 weeks antibodies with a two log increase in affinity and which retained their specificity” (Page 1, Abstract, lines 7-9). The outcome of “a Two log increase in affinity” is an embodiment of “altered affinity”.
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings, suggestions, and motivations from Saulquin in view of Rydzek and Shaimardanova for efficient altering of the binding affinity of antigen-binding molecules, then incorporate general laboratory techniques known in the art in order to purify and produce antigen-binding molecules with altered binding affinity after SHM-mediated affinity maturation and arrive at the claimed inventions.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Perli et al. (Continuous genetic recording with self-targeting CRISPR-Cas in human cells. Science. 2016 Sep 9;353(6304):aag0511; Hereinafter, Perli) in view of Rydzek (2019), in further view of Shaimardanova (2019).
Claim interpretation: The recitation of “one or more” is interpreted as only one of the recited elements “a)…”, “b)…”, “c)…” is required and the rest are optional. Nevertheless, Perli in view of Rydzek in further view of Shaimardanova renders all 3 elements obvious, see the reasoning below.
Perli (2016) teaches “a) a first heterologous nucleic acid sequence encoding a self-targeting guide RNA (stgRNA) operably linked to a first promoter” and ” b) a second heterologous nucleic acid sequence encoding a CRISPR-associated (Cas) protein operably linked to a second promoter, wherein the second promoter is induced by an immune response” when demonstrating the utility of stgRNA memory units that record signaling events in cells within live animals.
Regarding element a), Perli teaches the design of the stgRNA by stating “We built multiple variants of a S. pyogenes sgRNA-encoding DNA sequence with a 5′-GGG-3′ PAM located immediately downstream of the region encoding the 20-nt SDS and tested them for their ability to generate mutations at their own DNA locus.” (Page 2, left column, last 5 lines), hence, the stgRNA sequence variants with microbial origin is heterologous to the human HEK293T cells used to demonstrate the functions of the stgRNA (see recitation of HEK293T cell line below). The nucleic acid sequence containing stgRNA operably linked to a first promoter is taught by the recited disclosure (U6 promoter, U6p) and Fig. 4C below.
Regarding element b), Perli teaches “We adapted a well-established acute inflammation model … Immune cells that sense LPS release activator of the NF-κB pathway …plays an important role in coordinating responses in inflammation” (Page 5, right column, 2nd ¶, lines 1-2). Perli further teaches “We then built a clonal HEK 293T cell line containing an NF-κB-induced Cas9 expression cassette (NF-κB-Cas9 cells) and infected the cells with lentiviral particles encoding the 30nt-1 stgRNA at MOI ~0.3.” (Page 5, right column, 3rd ¶, lines 1-4), and the schematic of the 2 separate nucleic acid elements are shown in
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Fig. 4C (Page. 15, see above). This disclosure describes the inclusion of a NF-κB response element promoter (NF-κBREp, shown in Fig. 4C) inducible by an immune response operably linked to a Cas protein in a nucleic acid sequence.
However, Perli does not teach element “c) a third nucleic acid sequence encoding an antigen-binding molecule of interest”.
Rydzek (2019) teaches “a platform that enables rapid and high-throughput CAR-screening campaigns with … modified reporter cells with CD19-specific and ROR1-specific CARs, …” (Abstract, lines 4-14), wherein CAR refers to chimeric antigen receptor, which is an antigen-binding molecule well known in the art. Rydzek’s teachings have been discussed above.
However, neither Perli nor Rydzek teaches integrative nucleic acid construct comprising all 3 elements on the same construct.
The teachings of Shaimardanova have been discussed above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the strategy and nucleic acid construct embodiments of Perli using the high-throughput screening assay for antigen-binding molecule binding characteristics based on the common strategy of the NF-κB response element promoters used in both Perli and Rydzek and motivated by the improved efficiency to screen large mutant repertoire of an antigen-binding molecule and thereby arrive at the same inventions as claimed in the current application.
Since the recitation of “A” is defined in the specification as including plural reference (Page 15, ¶[0104]), the optional element(s) may or may not reside on the same nucleic acid construct as the required element. Whether the recited elements reside on the same, singular nucleic acid construct or on multiple, distinct nucleic acid constructs is a matter of routine laboratory optimization known in the art and in view of Shaimardanova for persons of ordinary skill in the art.
Claims 34, 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over Saulquin in view of Shaimardanova and Rydzek as applied to claims 1-5, 28-31, 43-44, 47, 49 above, in further view of INSERM (WO2020148207A1. Human monoclonal antibodies binding to hla-a2; Published 07/23/2020; Included in IDS filed on 08/05/2024; Hereinafter, INSERM).
The teachings of Saulquin, Shaimardanova, and Rydzek are discussed above.
Regarding claim 34, Saulquin does not teach that “the immune receptor comprises a B cell receptor, a chimeric antigen receptor, a membrane-bound antibody, and a membrane- bound immunoglobulin superfamily member”.
However, INSERM (2020) teaches “… chimeric antigen receptors (CARs) comprising an antigen binding domain of the antibody of the present invention” (Page 15, lines 16-17).
Regarding claims 37-38, INSERM further teaches: “in some embodiments, the antigen binding domain comprises a linker peptide. The linker peptide may be positioned between the light chain variable region and the heavy chain variable region” (Page 16, line 1-3). It is interpreted that the linker peptide is included in the nucleic acid encoding the structure in the form of a nucleic acid.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the strategy of Saulquin in view of Shaimardanova and Rydzek, in further view of INSERM to use populations of immune cells to generate affinity matured CAR-expressing cells involving multiple variable nucleic acid segments linked using a linker based on the teachings, suggestions, and motivations provided by INSERM, to improve the binding affinity of complex therapeutic immune antigen-binding molecules and arrive at the claimed inventions.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636