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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August 27, 2025 has been entered.
Detailed Action
This action is in response to the papers filed August 27, 2025.
Amendments
Applicant's amendments, filed August 27, 2025, is acknowledged. Applicant has cancelled Claims 1-22, 24-33, 35, and 37-40, and amended Claims 23.
Claims 23, 34, 36, and 41-42 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group II, Claim 23, drawn to a genomically modified human B cell, classified in C12N 2510/02.
Prior species election requirement has been rendered moot in light of Applicant’s amendments to the claims necessitating insertion of a nucleotide sequence encoding a heavy or light chain of a defined therapeutic monoclonal antibody into an endogenous heavy or light chain.
Priority
This application is a continuation of application 17/384,228, filed on July 23, 2021, now abandoned,
which is a continuation of application 16/152,273, filed on October 4, 2018, now abandoned,
which is a continuation of PCT/US2017/026011 filed on April 4, 2017.
The Examiner also acknowledges that PCT/US2017/026011 filed on April 4, 2017 is a continuation-in-part of application 15/161,213 filed on May 21, 2016, now abandoned,
which is a continuation-in-part of PCT/US2016/025920 filed on April 4, 2016.
See, for example, the Bib Data Sheet of applications 17/384,228 and 16/152,273.
Applicant’s claim for the benefit of a prior-filed application provisional application 62/142,882 filed on April 3, 2015 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Claim Objections
1. Claim 23 is objected to because of the following informalities:
As a first matter, where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m). The multiple ‘wherein’ clauses should be separated by line indentation.
As a second matter, the claim suffers from the absence of a conjunction between the first and second ‘wherein’ clauses.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
2. Claim(s) 23, 34, 36, and 41-42 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.
Applicant has amended Claim 23 to recite “transplantable population of genome-edited B cells”.
Either this is an inherent property of (that naturally flows from) the population(s) of genome-edited primary human B cells comprising the claimed genome-edits [structures], or it is not.
The claim denotes that not all populations of the genome-edited primary human B cells having the claimed genome-edits [structures] are “transplantable” [function].
To the extent it is not an inherent property (that naturally flows) from the population of genome-edited primary human B cells having the claimed genome-edits [structures], then something must change. The claim is considered to lack adequate written description for failing to recite the structure(s) that is/are necessary and sufficient to cause the recited functional language.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
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 by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claims fail to recite, and the specification fails to disclose, a first population of genome-edited primary human B cells comprising the claimed genome-edits [structures] which are not “transplantable…”, as opposed to a second population of genome-edited primary human B cells comprising the claimed genome-edits [structures] which are “transplantable…”.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
3. Claims 23, 34, 36, and 41-42 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Scholz et al (U.S. 2013/0143267; of record) in view of Buelow et al (U.S. 2007/0033661; of record), Hyde et al (U.S. 2013/0164277; of record), Ando et al (U.S. 2008/0159996; of record), Wang et al (available online August 25, 2014; of record), and Mandal et al (available online November 6, 2014; of record cited).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
Applicant has amended Claim 23 to recite “transplantable population of genome-edited B cells”.
A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. The phrase “transplantable…” is an intended use limitation, which does not contain any further structural limitations with respect to claimed primary human B cell(s) whose genome comprises a nucleic acid sequence encoding the variable regions of light and heavy chains of a heterologous therapeutic antibody recited in the independent claims (see MPEP §2114).
Instant specification fails to disclose a first population of genome-edited primary human B cells comprising the claimed gene-edits [structures] which are not “transplantable…”, as opposed to a second population of genome-edited primary human B cells comprising the claimed gene-edits [structures] which are “transplantable…”.
To the extent Applicant argues otherwise, see above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejection.
Applicant has amended Claim 23 to recite “transfected primary human B cells”.
The recitation of a process limitation in Claim 23 is not viewed as positively limiting the claimed product of Claim 23 absent a showing that the process of making recited in the dependent claims imparts a novel or unexpected property to the claimed product, as it is assumed that equivalent products are obtainable by multiple routes. The method in which the primary human B cell(s) whose genome comprises a nucleic acid sequence encoding the variable regions of light and heavy chains of a heterologous therapeutic antibody recited in the independent claims were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
There is no objective evidence that genome-edited primary human B cells comprising the claimed gene-edits [structures] made via transfection to introduce the heterologous nucleic acids are molecularly distinguishable from genome-edited primary human B cells comprising the claimed gene-edits [structures] made via other means of introducing the heterologous nucleic acids, e.g. electroporation, nucleofection, and/or transduction.
With respect to Claim 23, Scholz et al is considered relevant prior art for having disclosed and successfully demonstrated the ability of the ordinary artisan to genetically modify resting B cells, including primary human B cells (e.g. [0022], “a source of B cells is obtained from a subject”, “Examples of subjects include humans”), to express a transgene of interest, wherein the transgene of interest is a monoclonal antibody (e.g. [0076, 87], b12 anti-HIV-1 neutralizing antibody; Example 1, primary human B cells transduced to successfully produce the HIV neutralizing antibody b12).
Scholz et al does not disclose wherein the heterologous monoclonal antibody transgenes encoding the heavy and light chains are inserted into the endogenous heavy or light chain loci.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 23 and 36, Buelow et al is considered relevant prior art for having disclosed a population of somatic cells in which a human immunoglobulin locus transgene is either randomly inserted in the host B cell genome (as per Scholz et al) or replaces the endogenous immunoglobulin locus, e.g. via homologous recombination (e.g. [0112-113]), wherein the transgenic immunoglobulin locus encodes an immunoglobulin heavy chain or an immunoglobulin light chain (e.g. 0107]), and wherein the human immunoglobulin transgene encodes a monoclonal antibody (e.g. [0051, 55]). The exogenous immunoglobulins are expressed in B cells (e.g. [0038, 85]).
Similarly, Hyde et al is considered relevant prior art for having disclosed a population of B cells isolated from an individual ([0037], “isolating human B cells from an individual”), whereby the endogenous immunoglobulin heavy and light genes encoding a B cell receptor are deleted, being replaced via homologous recombination with a heterologous nucleic acid encoding the artisan’s immunoglobulin heavy and light chain genes [0037, 73].
The heterologous antibody is a monoclonal antibody (e.g. [0069], “isolated from the chromosomal DNA of a human B cell clone that produces the antibody”).
The artisan’s heterologous therapeutic immunoglobulin heavy and light chain genes may replace:
a) the endogenous functional immunoglobulin heavy and light chain genes (e.g. [0037], Example 5, [0111], anti-S. aureus PNAG antibody), and/or,
b) the endogenous non-functional immunoglobulin heavy and light chain genes (e.g. [0037], Example 2, [0082], anti-HCV antibody).
The artisan’s heterologous immunoglobulin heavy and light chain genes may be specific for influenza [0038], e.g. an anti-influenza broadly neutralizing antibody secreted from the B cell ([0042], “secreted anti-influenza broadly neutralizing antibodies”), or HCV (e.g. [0082], the replacement Ig genes…encode a secreted anti-HCV antibody), or S. aureus pathogen (e.g. Example 5, [0111], anti-S. aureus PNAG antibody, [0107], secreted immunoglobulins to methicillin-resistant S. aureus (MRSA)).
Hyde et al disclosed and successfully demonstrated the ability to transfect primary B cells with a nucleic acid encoding an immunoglobulin molecule (e.g. [0045, 47, 49], “transfected with”).
With respect to the ability of the ordinary artisan to edit the genome of primary human B cells with a reasonable expectation of success:
Ando et al is considered relevant prior art for having disclosed the use of ZFNs to edit the genome of primary human T cells, thereby resulting in the targeted insertion of an exogenous nucleic acid sequence into a targeted location of the T cell genome (Example 5), and disclosed the ZFNs may also be used in B cells and other T cell subtypes [0122].
Wang et al is considered relevant prior art for having successfully demonstrated the use of the CRISPR/Cas9 system to edit the genome of human B cells, e.g. Raji cells (e.g. Figures 1-2).
Mandal et al is considered relevant prior art for having successfully demonstrated the ability of the ordinary artisan to use the CRISPR/Cas9 gene editing system to target and edit the artisan’s gene(s) of interest in primary human T cells and primary human hematopoietic stem cells (HSCs) (entire paper, Graphical Abstract; Summary, “primary human CD4+ T cells”).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in molecular biology, immunology, cell biology, and gene editing technologies. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to substitute a first vector genomic location in which to insert the artisan’s therapeutic antibody heavy and light chain genes, e.g. random integration, as disclosed by Scholz et al and Buelow et al, with a second genomic location in which to insert the artisan’s therapeutic antibody heavy and light chain genes, to wit, replacement of the endogenous immunoglobulin heavy and light chain genes, as disclosed by Buelow et al and Hyde et al, in primary human B cells with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. An artisan would be motivated to substitute to substitute a first vector genomic location in which to insert the artisan’s therapeutic antibody heavy and light chain genes, e.g. random integration, with a second genomic location in which to insert the artisan’s therapeutic antibody heavy and light chain genes, to wit, replacement of the endogenous immunoglobulin heavy and light chain genes, in primary human B cells because those or ordinary skill in the art previously recognized and successfully reduced to practice the scientific and technical concepts of inserting the artisan’s therapeutic antibody heavy and light chain genes into the endogenous immunoglobulin heavy and light chain loci, and Buelow et al disclosed a population of somatic cells in which a human immunoglobulin locus transgene is either randomly inserted in the host B cell genome (as per Scholz et al) or replaces the endogenous immunoglobulin locus, e.g. via homologous recombination (e.g. [0112-113]).
It is obvious to one of ordinary skill in the art to choose from a finite number of identified, predictable options because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipate success, it is likely that product not of innovation but of ordinary skill and common sense.” The ordinary artisan previously recognized that there is a finite list of potential options, e.g. random integration or insertion into the endogenous immunoglobulin heavy and light chain loci, whereby the ordinary artisan could have pursued the known potential options with a reasonable expectation of success, as the antibody transgenes were successfully demonstrated by the cited prior art to be expressed from genetically modified B cells via genomic integration using both options, and the number of potential options from which to choose is neither astronomical nor insurmountable, and given the guidance of the cited prior art, it would only be routine experimentation to integrate the artisan’s therapeutic antibody heavy and light chain genes into the endogenous immunoglobulin heavy and light chain genes.
Those of ordinary skill in the art previously recognized and/or successfully reduced to practice that gene editing technologies such as ZFN nucleases and CRISPR/Cas9 system are able to edit the genome of human immune cells, including T and B cells, including primary human immune cells. Thus, it is considered that those of ordinary skill in the art would have a reasonable expectation of success for gene editing technologies such as ZFN nucleases and CRISPR/Cas9 system to edit the genome of primary human B cells, there being no objective evidence of undue experimentation in the art.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 34, Scholz et al disclosed wherein the genetically modified primary human B cells of the population secrete a defined therapeutic antibody encoded by the inserted sequences (e.g. [0018], “develop into plasma cells (activated B cells) that secrete abundant amounts of the protein encoded by the nucleic acid of interest”; [0031], “B cell into an antibody secreting cell”; Example 1, [0128], “able to differentiate the [genetically] modified quiescent B cell into a plasma cells”; Figure 1, b12 antibody production).
Hyde et al disclosed the artisan’s heterologous immunoglobulin heavy and light chain genes may be specific for influenza [0038], e.g. an anti-influenza broadly neutralizing antibody secreted from the B cell ([0042], “secreted anti-influenza broadly neutralizing antibodies”), or HCV (e.g. [0082], the replacement Ig genes…encode a secreted anti-HCV antibody), or S. aureus pathogen (e.g. Example 5, [0111], anti-S. aureus PNAG antibody, [0107], secreted immunoglobulins to methicillin-resistant S. aureus (MRSA)).
With respect to Claim 41, Buelow et al disclosed a population of somatic cells in which a human immunoglobulin locus transgene is either randomly inserted in the host B cell genome ([0112], as per Scholz et al) or replaces the endogenous immunoglobulin locus, e.g. via homologous recombination (e.g. [0113]), wherein the transgenic immunoglobulin locus encodes an immunoglobulin heavy chain or an immunoglobulin light chain (e.g. 0107]), which necessarily reads upon one or more of the endogenous heavy or light chain loci selected from the group consisting of IGHV, IGHD, IGHJ, IGKV, and IGKJ.
Hyde et al disclosed a population of B cells isolated from an individual ([0037], “isolating human B cells from an individual”), whereby the endogenous immunoglobulin heavy and light genes encoding a B cell receptor are deleted, being replaced via homologous recombination with a heterologous nucleic acid encoding the artisan’s immunoglobulin heavy and light chain genes [0037, 73], which necessarily reads upon one or more of the endogenous heavy or light chain loci selected from the group consisting of IGHV, IGHD, IGHJ, IGKV, and IGKJ.
With respect to Claim 42, Scholz et al disclosed wherein the monoclonal antibody is specific for HIV-1 (e.g. [0076, 87], b12 anti-HIV-1 neutralizing antibody; Example 1, primary human B cells transduced to successfully produce the HIV neutralizing antibody b12).
Hyde et al disclosed the artisan’s heterologous immunoglobulin heavy and light chain genes may be specific for influenza [0038], e.g. an anti-influenza broadly neutralizing antibody secreted from the B cell ([0042], “secreted anti-influenza broadly neutralizing antibodies”), or HCV (e.g. [0082], the replacement Ig genes…encode a secreted anti-HCV antibody), or S. aureus pathogen (e.g. Example 5, [0111], anti-S. aureus PNAG antibody, [0107], secreted immunoglobulins to methicillin-resistant S. aureus (MRSA)).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Response to Arguments
Applicant argues that because Scholz et al transduced the primary B cells with a virus encoding the therapeutic antibody, resulting in random integration, Scholz et al teach away from the instantly claimed cells that comprise a gene replacement or substitution.
Applicant’s argument(s) has been fully considered, but is not persuasive. A prior art reference that "teaches away" from the claimed invention is a significant factor to be considered in determining obviousness; however, "the nature of the teaching is highly relevant and must be weighed in substance. That Scholz et al disclosed the use of a virus encoding the therapeutic antibody to transduce the primary human B cells, resulting in random integration, does not constitute a teaching away from the claimed cells because nowhere in the Scholz et al disclosure does it criticize, discredit, or otherwise discourage the solution now claimed. In fact, Scholz et al disclosed that the B cells may be transfected with heterologous nucleic acids (e.g. [0031], “transfection into”; [0053], “co-transfection with”; [0091, 103], “transfected with”).
Applicant argues that Scholz et al and Ando et al rely on viral vectors, not transfection, to introduce the genes into the target host cells.
Applicant’s argument(s) has been fully considered, but is not persuasive. The recitation of a process limitation in Claim 23 is not viewed as positively limiting the claimed product of Claim 23 absent a showing that the process of making recited in the dependent claims imparts a novel or unexpected property to the claimed product, as it is assumed that equivalent products are obtainable by multiple routes. The method in which the primary human B cell(s) whose genome comprises a nucleic acid sequence encoding the variable regions of light and heavy chains of a heterologous therapeutic antibody recited in the independent claims were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
There is no objective evidence that genome-edited primary human B cells comprising the claimed gene-edits [structures] made via transfection to introduce the heterologous nucleic acids are molecularly distinguishable from genome-edited primary human B cells comprising the claimed gene-edits [structures] made via other means of introducing the heterologous nucleic acids, e.g. electroporation, nucleofection, and/or transduction.
Applicant argues that Buelow et al selected the cells in which the transgene has replaced the corresponding Ig locus by homologous recombination; whereas, Applicant specifically did not select clones from the transfected population.
Applicant’s argument(s) has been fully considered, but is not persuasive.
As a first matter, instant claims do not prohibit the claimed cells from being selected from cells that do not comprise the desired gene-edit.
As a second matter, instant claims are directed to a product, not a method of making.
As discussed above, the method in which the primary human B cell(s) whose genome comprises a nucleic acid sequence encoding the variable regions of light and heavy chains of a heterologous therapeutic antibody recited in the independent claims were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
There is no objective evidence that genome-edited primary human B cells comprising the claimed gene-edits [structures] made via argued absence of selection to purify are molecularly distinguishable from genome-edited primary human B cells comprising the claimed gene-edits [structures] made via genome-edited primary human B cells comprising the claimed gene-edits [structures] made via argued absence of selection to purify
Applicant argues that additional cell divisions can result in karyotype abnormalities, and such cells cannot be administered to a patient.
Applicant’s argument(s) has been fully considered, but is not persuasive. Instant claims place no requirement on the number of cell divisions before and/or after the genome edit, nor do exclude “karyotype abnormalities”, whatever vague and however few change(s) it might be, per Applicant’s hypothetical argument. Applicant fails to provide objective evidence that the B cells expressing heterologous antibodies of the cite prior art are not “human-transplantable”.
The Examiner provides the following references to rebut applicant’s arguments
regarding the state of the prior art. Note: these references are not considered a part of the 103 rejection but are solely provided to rebut applicant’s argument(s).
Neron et al (Large-Scale In Vitro Expansion of Polyclonal Human Switched-Memory B Lymphocytes, PLoS ONE 7(12): e51946, 9 pages, doi:10.1371/journal.pone.0051946, December 2012) is considered relevant prior art for having taught the ability to in vitro expand primary human B cells, without immortalization, for as many as 65 days, (e.g. pg 5, col. 1, Results) providing large-scale expansion of the primary human B lymphocytes by almost 10^9-fold (e.g. Abstract; Figure 2A-B). Neron et al taught that the culture conditions could allow the expansion of autologous effector human B lymphocytes to be used in cell-based therapies (e.g. pg 8, col. 2, Conclusion).
Kippen et al (Massive ex Vivo Expansion of Human Natural Regulatory T Cells (Tregs) with Minimal Loss of in Vivo Functional Activity, Science Translational Medicine 3(83): e83ra41, 9 pages, 10.1126/scitranslmed.3001809, available online May 18, 2011) is considered relevant prior art for having taught the ability to in vitro expand primary human Treg cells, without immortalization, by us much as 80-fold, yielding about 2x10^10 cells (e.g. Abstract). Kippen et al taught Treg cells were restimulated and expanded at least 4 times, and the culture conditions efficiently produce an off-the-shelf cellular therapy (Abstract).
Thus, Applicant’s argued concern over the formation of hypothetical karyotypic abnormalities due to additional cell divisions, thereby precluding the B cells from being administered to a patient, is contradicted by the prior art and state of the art in cellular therapeutics developing off-the-shelf therapeutic lymphocyte populations for clinical medicine, as they are suitable for transplantation into humans.
Applicant argues that the B cells of Hyde et al are immortalized by infection with EBV, and therefore are not primary B cells.
Applicant’s argument(s) has been fully considered, but is not persuasive. While Hyde et al disclosed one embodiment of immortalizing B cells with EBV, such is not limiting. Rather, Hyde et al disclosed other methods, e.g. protocol 2, protocol 3, and protocol 4 (e.g. 0045-49]) which do not require immortalizing by infection with EBV.
Applicant argues that because Hyde et al’s B cells are immortalized by infection with EBV, the cells are not compatible with human transplantation, and thus teach away from the instantly claimed invention.
Applicant’s argument(s) has been fully considered, but is not persuasive. Hyde et al disclosed other methods, e.g. protocol 2, protocol 3, and protocol 4 (e.g. 0045-49]) which do not require immortalizing by infection with EBV, and thus do not teach away from the instantly claimed invention.
Applicant argues that Wang et al uses immortalized cell lines, not primary cells, and Mandal et al uses gene editing to ablate genes, not insert coding sequences into the genome.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Ando et al disclosed the use of ZFNs to edit the genome of primary human T cells, thereby resulting in the targeted insertion of an exogenous nucleic acid sequence into a targeted location of the T cell genome (Example 5), and disclosed the ZFNs may also be used in B cells and other T cell subtypes [0122].
Wang et al is considered relevant prior art for having successfully demonstrated the use of the CRISPR/Cas9 system to edit the genome of human B cells, e.g. Raji cells (e.g. Figures 1-2).
Mandal et al is considered relevant prior art for having successfully demonstrated the ability of the ordinary artisan to use the CRISPR/Cas9 gene editing system to target and edit the artisan’s gene(s) of interest in primary human T cells and primary human hematopoietic stem cells (HSCs) (entire paper, Graphical Abstract; Summary, “primary human CD4+ T cells”).
Thus, prior to the effective filing date of the instantly claimed invention, those of ordinary skill in the art previously recognized the ability to perform gene-editing in human B cells, including primary human cells, including lymphocytes, with a reasonable expectation of success.
Applicant argues that the Examiner has exercised impermissible hindsight.
Applicant’s argument(s) has been fully considered, but is not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant argues that Scholz taught the use of retroviral gene transfer.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Scholz et al is considered relevant prior art for having disclosed and successfully demonstrated the ability of the ordinary artisan to genetically modify resting B cells, including primary human B cells (e.g. [0022], “a source of B cells is obtained from a subject”, “Examples of subjects include humans”), to express a transgene of interest, wherein the transgene of interest is a monoclonal antibody (e.g. [0076, 87], b12 anti-HIV-1 neutralizing antibody; Example 1, primary human B cells transduced to successfully produce the HIV neutralizing antibody b12).
Applicant argues that Beulow is directed to non-human transgenic animals.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner must determine what is "analogous prior art" for the purpose of analyzing the obviousness of the subject matter at issue. **>"Under the correct analysis, any need or problem known in the field of endeavor at the time of the invention and addressed by the patent [or application at issue] can provide a reason for combining the elements in the manner claimed. " KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). Thus a reference in a field different from that of applicant's endeavor may be reasonably pertinent if it is one which, because of the matter with which it deals, logically would have commended itself to an inventor's attention in considering his or her invention as a whole.<
Buelow et al is considered relevant prior art for having disclosed a population of somatic cells in which a human immunoglobulin locus transgene is either randomly inserted in the host B cell genome (as per Scholz et al) or replaces the endogenous immunoglobulin locus, e.g. via homologous recombination (e.g. [0112-113]), wherein the transgenic immunoglobulin locus encodes an immunoglobulin heavy chain or an immunoglobulin light chain (e.g. 0107]), and wherein the human immunoglobulin transgene encodes a monoclonal antibody (e.g. [0051, 55]). The exogenous immunoglobulins are expressed in B cells (e.g. [0038, 85]).
Furthermore, Hyde et al is considered relevant prior art for having disclosed a population of B cells isolated from an individual ([0037], “isolating human B cells from an individual”), whereby the endogenous immunoglobulin heavy and light genes encoding a B cell receptor are deleted, being replaced via homologous recombination with a heterologous nucleic acid encoding the artisan’s immunoglobulin heavy and light chain genes [0037, 73].
Applicant argues that Hyde teaches only prophetic examples.
Applicant’s argument(s) has been fully considered, but is not persuasive. The specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970).
A reference contains an "enabling disclosure" if the public was in possession of the claimed invention before the date of invention. "Such possession is effected if one of ordinary skill in the art could have combined the publication's description of the invention with his [or her] own knowledge to make the claimed invention." In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
Ando et al disclosed the use of ZFNs to edit the genome of primary human T cells, thereby resulting in the targeted insertion of an exogenous nucleic acid sequence into a targeted location of the T cell genome (Example 5), and disclosed the ZFNs may also be used in B cells and other T cell subtypes [0122].
Wang et al successfully demonstrated the use of the CRISPR/Cas9 system to edit the genome of human B cells, e.g. Raji cells (e.g. Figures 1-2).
Mandal et al successfully demonstrated the ability of the ordinary artisan to use the CRISPR/Cas9 gene editing system to target and edit the artisan’s gene(s) of interest in primary human T cells and primary human hematopoietic stem cells (HSCs) (entire paper, Graphical Abstract; Summary, “primary human CD4+ T cells”).
Thus, no undue experimentation is required.
Applicant argues that neither Ando, Wang, nor Mandal address the issues relevant for administering a therapeutic cell population to human patients.
Applicant’s argument(s) has been fully considered, but is not persuasive. Instant claims are directed to a cellular product, not a method of use.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
4. Claims 23, 34, 36, and 41-42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 53-58 and 60-67 of copending Application No. 18/141278 (reference application; claim set filed August 26, 2025). Although the claims at issue are not identical, they are not patentably distinct from each other.
‘278 recites primary human B cells whose genomes have been modified with insertion of heterologous nucleic acids encoding heavy and light chains of a therapeutic monoclonal antibody, each of which comprise at least the respective heavy and light chain variable regions. ‘278 claims do not exclude the presence of other heavy and light chain domains present in the instantly claimed antibodies.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Citation of Relevant Prior Art
5. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Li et al (Optimization of Genome Engineering Approaches with the CRISPR/Cas9 System, PLoS One 9(8): e105779; 10 pages, available online August 28, 2014; of record) is considered relevant prior art for having taught optimization of the CRISPR/Cas9 system for genome engineering (Title), wherein said optimization includes comparison of different guide RNA target sequences, individually or in combination, e.g. GFP KO gRNAs (Table 1; pg 3, col. 2), as such is common practice in the art (See also citation #13 to Mali et al, “target specificity screening”). Li et al taught that the cleavage efficiency “varied based on the transfection efficiency” (pg 3, col. 2).
Schumann et al (Generation of knock-in primary human T cells using Cas9 ribonucleoproteins, Proc. Nat’l Acad. Sci. 112(33): 10437-10442, available online July 27, 2015; of record in IDS of parent application 16/152,273) is considered relevant prior art for having taught that the editing ef