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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 June 20, 2025 has been entered.
Detailed Action
This action is in response to the papers filed June 20, 2025.
Amendments
Applicant's response and amendments, filed June 20, 2025, is acknowledged.
Applicant has cancelled Claims 2, 4-7, 16-17, 22-23, 25, 27, 30-31, 41-42, 44-47, 49-55, and 58-65, amended Claims 1, 26, and 28, withdrawn Claims 8-15, 18, 21, 26, 28-29, 32-40, 43, 48, and 56-57, and added new claims, Claims 66-71.
Claims 1, 3, 8-15, 18-21, 24, 26, 28-29, 32-40, 43, 48, 56-57, and 66-71 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group IV, claim(s) 1-3, 8-15, 17-21, 24-29, 32-40, 43, drawn to a method for editing the genome of an isolated B lymphocyte comprising the steps of:
(i) activating endogenous activation-induced cytidine deaminase of the B lymphocyte;
and
(ii) introducing a DNA molecule comprising a nucleotide sequence encoding a (poly)peptide of interest into the B lymphocyte.
Within Group IV, Applicant has elected the following species, wherein:
ii) the alternative agent species to activate AICD is a cytokine, as recited in Claims 25-26 and 28; and
iv) the alternative method step species is wherein the method does not involve an exogenous nuclease and/or an engineered nuclease, such as a CRISPR nuclease, a zinc finger nuclease, a transcription activator-like nuclease or a meganuclease, as recited in Claim 2.
In a telephonic interview with Applicant’s representative, Michelle LeCointe at 206-622-4900 on April 24, 2024, it was confirmed that Applicant has elected the following species:
i) the alternative polypeptide species encoded by DNA molecule comprises or consists of a pathogen binding domain, as recited in Claim 17; and
iii) the alternative DNA structural embodiment(s) species is a DNA molecule that is a linear or linearized DNA molecule, as recited in Claim 3.
Claims 1, 3, 8-15, 18-21, 24, 26, 28-29, 32-40, 43, 48, 56-57, and 66-71 are pending.
Claims 8-15, 18, 21, 26, 28-29, 32-40, 43, 48, and 56-57 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1, 3, 19-20, 24, and 66-71 are under consideration.
Priority
This application is a 371 of PCT/EP2019/064109 filed May 29, 2019.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d). A copy of foreign patent application PCT/EP2018/064299 filed May 30, 2018 has been filed with the instant application.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on June 20, 2025 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Objections
1. Claim 1 is objected to because of the following informalities: The claim recites “BAFF” and “APRIL”; however, the claim does not first identify the AICD activator by its complete name prior to using its acronym. The abbreviation should be spelled out in the first appearance of the claims and should be followed by the abbreviation in parentheses. See, for example, Claim 3, “double strand DNA (dsDNA)”.
Appropriate correction is required.
2. Claim 3 is objected to because of the following informalities: The claim lacks punctuation between “(ssDNA) or a double”.
Thus, the claim appears to suffer from ambiguity for want of a comma or semi-colon to avoid the ambiguity that a missing serial comma would otherwise create. See, for example, O'Connor v. Oakhurst Dairy.
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.
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.
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.
3. Claim 3 is 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 3 recites the broad recitation “linear or linearized DNA molecule” and the claim also recites “single strand DNA molecule (ssDNA)” and “dsDNA having blunt ends or overhangs” which is/are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The Examiner notes that it is axiomatic natural law of chemistry and biology that a linear/linearized DNA molecule will only have two types of ends: blunt or overhang. Thus, recitation of “having blunt ends or overhang” is internally redundant to the linear/linearized dsDNA molecule.
4. Claim 69 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 69 recites dependency upon Claim 70.
The order of the claims is not in accordance with MPEP §608.01(m), nor complies with 35 U.S.C. 112(d).
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 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], 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 claims should be arranged in order of scope so that the first claim presented is the least restrictive.
Applicant should correct the claim dependency to comply with 35 U.S.C. 112(d) and MPEP §608.01(m). See, for example, Claims 66-68.
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.
5. Claim 71 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 71 recites the limitation “wherein restimulating in (iii)…”. There is insufficient antecedent basis for this limitation in the claim because the claim recites dependency upon itself.
Appropriate correction is required.
6. Claims 69-71 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.
Claims 70-71 recite the limitation “wherein restimulating in (iii)…”. There is insufficient antecedent basis for this limitation in the claims because Claim 1, step (iii), is an introducing step, not a restimulating step.
Claim 70 recites the limitation “activating in (ii)…”. There is insufficient antecedent basis for this limitation in the claims because Claim 1, step (ii), is restimulating step, not a activating step.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Appropriate correction is required.
7. Claims 66-69 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 66 recites the limitation “wherein the cytokine is added…”. There is insufficient antecedent basis for this limitation in the claims because it is unclear if the limitation refers back to Claim 1, step (i), or Claim 1, step (ii).
Claim 67 recites the limitation “wherein the cytokine is re-added…”. There is insufficient antecedent basis for this limitation in the claims because it is unclear if the limitation refers back to Claim 1, step (i), or Claim 1, step (ii).
Claim 68 recites the limitation “wherein the isolated B lymphocytes is restimulated…”. There is insufficient antecedent basis for this limitation in the claims because it is unclear if the limitation refers back to Claim 1, step (i), Claim 1, step (ii), or Claim 1, step (iii).
Claim 69 recites the limitation “wherein the isolated B lymphocytes is further restimulated…”. There is insufficient antecedent basis for this limitation in the claims because it is unclear if the limitation refers back to Claim 1, step (i), Claim 1, step (ii), or Claim 1, step (iii), or if this is a new step, e.g. step (iv).
Appropriate correction is required.
8. Claim 20 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 1 recites a method for editing the genome of an isolated B lymphocyte comprising the step(s) of:
(iii) introducing a DNA molecule comprising a nucleotide sequence encoding a (poly)peptide of interest into a switch region of an immunoglobulin gene locus of the B lymphocyte.
Claim 20, dependent upon Claim 1, recites wherein the method comprises obtaining an engineered B lymphocyte whose genome comprises the nucleotide sequence encoding the (poly)peptide of interest.
Claim 20 fails to further limit Claim 1 because it is axiomatic that having performed the method of Claim 1 on the isolated B lymphocyte, one has necessarily obtained an isolated engineered B lymphocyte whose genome comprises the nucleotide sequence encoding the (poly)peptide of interest.
The specification fails to disclose a method of Claim 1 that does not achieve the limitation(s) of Claim 20.
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.
9. Claim 24 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 1 recites a method for editing the genome of an isolated B lymphocyte comprising the step(s) of:
(i) activating endogenous activation-induced cytidine deaminase of the B lymphocyte;
wherein the activator of activation-induced cytidine deaminase is a cytokine selected from the group consisting of CD40L, IL4, IL2, IL21, BAFF, APRIL, CD30L, TGFbeta1, 4-lBBL, IL6, IL7, ILl0, IL13, c-Kit, FLT-3, IFNalpha and any combination thereof; and
wherein the cytokine is added to the isolated B lymphocyte at a concentration of about 0.0lng/ml to about 20ng/mL; and
(ii) restimulating the isolated B lymphocyte with the cytokine at about 12 hours to about 24 hours after initial adding of the cytokine;
wherein the cytokine is re-added at a concentration of about 0.0lng/ml to about 20ng/mL.
Claim 24, dependent upon Claim 1, recites wherein the B lymphocyte is cultured in a culture medium comprising the AICD activator.
Claim 24 fails to further limit Claim 1 because those of ordinary skill in the art that it is axiomatic that B lymphocyte is activated and/or restimulated in a culture medium comprising the AICD activator for the recited time period of Claim 1.
The specification fails to disclose a method of Claim 1 that does not comprise a culture medium in steps (i) and/or (ii).
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.
10. Claims 1, 3, 19-20, 24, and 66-71 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 1 recites the broad recitation “exogenous nuclease and/or an engineered nuclease” and the claim also recites “such as a CRISPR…”, which is/are the narrower statement(s) of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The instant claims as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Appropriate correction is required.
11. Claims 1, 3, 19-20, 24, and 66-71 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to recite a method for editing the genome of an isolated B lymphocyte comprising the steps of:
(i) activating endogenous activation-induced cytidine deaminase of the B lymphocyte;
wherein the activator of activation-induced cytidine deaminase is a cytokine selected from the group consisting of CD40L, IL4, IL2, IL21, BAFF, APRIL, CD30L, TGFbeta1, 4-lBBL, IL6, IL7, ILl0, IL13, c-Kit, FLT-3, IFNalpha and any combination thereof; and
wherein the cytokine is added to the isolated B lymphocyte at a concentration of about 0.0lng/ml to about 20ng/mL;
(ii) restimulating the isolated B lymphocyte with the cytokine at about 12 hours to about 24 hours after initial adding of the cytokine;
wherein the cytokine is re-added at a concentration of about 0.0lng/ml to about 20ng/mL; and
(iii) introducing a DNA molecule comprising a nucleotide sequence encoding a (poly)peptide of interest into a switch region of an immunoglobulin gene locus of the B lymphocyte,
wherein the method does not involve an exogenous nuclease and/or an engineered nuclease.
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 are broad for encompassing an enormous genus of structurally different exogenous DNA molecules introduced into the B lymphocytes that are to be introduced into a switch region of an immunoglobulin gene locus, including, but not limited to, viral vectors, e.g. retrovirus, lentivirus, herpes virus, adenovirus, AAV (e.g. pg 25, lines 25-32), circular or linear plasmids (e.g. pg 29, lines 19-20), or single-stranded DNA molecules (e.g. pg 29, line 30).
The claims are enormously broad for encompassing an enormous genus of structurally and functionally diverse agents, recited at a high level of generality (e.g. Claim 25), including the large genus of agent (pg 88, lines 3-20), by which AICD is to be activated in the B lymphocytes, whereby said B cells are exposed to said enormous genus of agents at an enormous concentration range, respectively (e.g. Claim 27) for a broad range of time (e.g. pg 87, line 27, up to 10 days prior to and/or after the step of introducing the DNA molecule into the B cells).
Frecha et al (Efficient and stable transduction of resting B lymphocytes and primary chronic lymphocyte leukemia cells using measles virus gp displaying lentiviral vectors, Blood 114(15): 3173-3180, 2009; of record) taught a method for editing the genome of an isolated B lymphocyte comprising the steps of:
(i) activating endogenous activation-induced cytidine deaminase of the B lymphocyte with an IL-2 cytokine at a concentration of 1ng/ml for at least 48 hours; and
(ii) introducing a DNA molecule comprising a nucleotide sequence encoding a (poly)peptide of interest into the B lymphocyte (e.g. pg 3174, col. 1, Methods, Transduction assays).
The specification discloses the cells are cultured with the cytokine for at least 12, 24, 36, 48, or 72 hours prior to transfection (e.g. pg 88, line 20).
Instant specification fails to disclose an element of criticality for a first IL-2 stimulating step of up to 24 hours followed by a second IL-2 stimulating step for up to 24 hours, and then introducing the nucleic acid molecule into the B cell, as opposed to a first IL-2 stimulating step of up to 48 hours, and then introducing the nucleic acid molecule into the B cell. Rather, those of ordinary skill in the art immediately recognize that in both contexts, the B cells are stimulated with the IL-2 for at least 48 hours prior to the step of introducing the nucleic acid into the B cells.
Frecha et al taught wherein the method does not involve an exogenous nuclease and/or an engineered nuclease, such as a CRISPR nuclease, a zinc finger nuclease, a transcription activator-like nuclease or a meganuclease (entire paper).
Frecha et al taught wherein the DNA molecule is introduced into the B cells using a lentiviral vector (entire paper), whereby those of ordinary skill in the art immediately recognize the lentiviral vector to be a linear genome molecule, and upon reverse-transcription, yields a linear DNA molecule prior to insertion into the host cell genome.
The specification discloses that it is natural law of cell biology (e.g. pg 26, lines 19-27, “occurs by natural mechanisms…”) that, upon activation of AICD in the B lymphocyte, the exogenous nucleic acid is introduced into the switch region of an immunoglobulin gene locus of the B lymphocyte.
Frecha et al performed the positively recited artisan action-taking steps of (i) activating AICD and (ii) introducing a DNA molecule into the B lymphocytes, wherein the method does not involve an exogenous nuclease, and Applicant admits that it is natural law of cell biology (e.g. pg 26, lines 19-27, “occurs by natural mechanisms…”) that, upon activation of AICD in the B lymphocyte, the exogenous nucleic acid is introduced into the switch region of an immunoglobulin gene locus of the B lymphocyte.
However, Applicant argues that Frecha et al do not teach the resulting insertion of the exogenous DNA molecule into a switch region of an immunoglobulin locus in the B cell.
Thus, Frecha et al would appear to evidence that the instant method recited at a high level of generality does not work as claimed.
King et al (U.S. 2013/0102031; of record) disclosed a method for editing the genome of an isolated B lymphocyte (e.g. [0068], “the mammalian cell can be a human lymphoid cell, such as a B-cell or a cell line of a pre-B lymphocyte origin”) comprising the steps of:
(i) activating endogenous activation-induced cytidine deaminase (e.g. [0044], “AID can be endogenous to the cell”; [0070], “providing a cell that expresses or can be induced to express AID”) of the B lymphocyte; and
(ii) introducing a DNA molecule comprising a nucleotide sequence encoding a (poly)peptide of interest into the B lymphocyte (e.g. [0023, 43], “contacting the cell in vitro with the…nucleic acid sequence encoding the polypeptide”; [0050], “upon expression of AID in the cell, one or more insertion mutations and/or deletion mutations are introduced into the nucleic acid sequence encoding the polypeptide”).
King et al do not disclose wherein the method requires involvement of an exogenous nuclease and/or an engineered nuclease, such as a CRISPR nuclease, a zinc finger nuclease, a transcription activator-like nuclease or a meganuclease. Rather, other forms of integrating vectors may be used (e.g. [0056, 62]; Example 2, plasmid).
King et al performed the positively recited artisan action-taking steps of (i) activating AICD and (ii) introducing a DNA molecule into the B lymphocytes, wherein the method does not involve an exogenous nuclease, and Applicant admits that it is natural law of cell biology (e.g. pg 26, lines 19-27, “occurs by natural mechanisms…”) that, upon activation of AICD in the B lymphocyte, the exogenous nucleic acid is introduced into the switch region of an immunoglobulin gene locus of the B lymphocyte.
However, Applicant argues that King et al do not teach the resulting insertion of the exogenous DNA molecule into a switch region of an immunoglobulin locus in the B cell.
Thus, it is axiomatic that the broadly claimed method presently recited, and encompassed by the cite prior art, does not work. Something of the instantly claimed method must change.
The specification working example (Example 1) is directed to the use of 8ng/ml IL-4, apparently to activate AICD, for at least 5 days prior to the introduction of at least 1ug single-stranded DNA oligonucleotide (long single strand DNA (LsODN)) by nucleofection, being further stimulated with at least 8ng/ml IL-4 for at least 9 after the DNA was introduced (pg 109, lines 1-10; Figures 3-4).
The specification working example (Example 2) is directed to the use of 8ng/ml IL-4, apparently to activate AICD, and the introduction of a linear, double-stranded DNA by nucleofection (pg 110, lines 30-31; Figures 3 and 5).
However, independent Claim 1 is far broader in scope to the actual reductions to practice, and, Applicant argues that the cited prior art, despite having performed the recited action-taking steps, do not achieve the claimed result of introducing DNA molecule into a switch region of an immunoglobulin gene locus.
Hasham et al (Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination, Nature Immunology 11(9): 820-826, 2010; of record) is considered relevant prior art for having taught that AICD naturally causes widespread genomic double-stranded breaks, not just within the switch region of an immunoglobulin gene locus, because it has no known target-site specificity, but rather acts promiscuously (e.g. Abstract).
Similarly, Staszewski et al (Activation-Induced Cytidine Deaminase Induces Reproducible DNA Breaks at Many Non-Ig Loci in Activated B Cells, Molecular Cell 41: 232-242, 2011) is considered relevant prior art for having taught that AICD induces DNA breaks at many non-immunoglobulin loci in activated B cells (e.g. Title; Abstract, “genome-wide AID-dependent DSBs”; pg 233, col. 2, “we identified 364 reproducible AID-dependent…”).
Thus, it would seem that the broadly claimed method of activating AICD would naturally yield insertions of the heterologous DNA molecule to a multitude of genomic locations, not just the switch region of an immunoglobulin locus.
Buschle et al (Transfection and gene expression in normal and malignant primary B lymphocytes, J. Immunol. Methods 133: 77-85, 1990) is considered relevant prior art for having taught a method of introducing the artisan’s DNA molecule of interest, to wit, plasmids, into isolated B cells, the method comprising the step of activating endogenous AICD in the B cells for 3 days with TPA prior to electroporation (e.g. pg 78, col. 2, Methods, Cell Stimulation).
Nonaka et al (Activation-induced cytidine deaminase promotes oncogenesis of ultraviolet light-independent epidermal cancer from keratinocytic and melanocytic origin, FEBS Journal 279(Suppl 1): Abstract p13-8, pg 290, 2012) is considered relevant prior art for having taught that TPA inherently and naturally activates AICD.
Buschle et al do not teach wherein the artisan’s DNA molecule of interest, to wit, plasmids, are introduced into a switch region of an immunoglobulin gene locus of the B lymphocytes.
McMahon et al (Transient transfection of murine B lymphocyte blasts as a method for examining gene regulation in primary B cells, J. Immunol. Methods 179: 251-259, 1995) is considered relevant prior art for having taught a method of introducing the artisan’s DNA molecule of interest, to wit, plasmids, into isolated B cells, the method comprising the step of activating endogenous AICD in the B cells for 3 days with LPS prior to transfection (e.g. pg 252, col. 2, Methods, 2.3 Proliferation assay).
Similarly, Li et al (Efficient transduction of murine B lymphocytes and B lymphoma lines by modified adenoviral vectors: enhancement via targeting to FcR and heparan-containing proteins, Gene Therapy 8: 938-945, 2001) is considered relevant prior art for having taught a method of introducing the artisan’s DNA molecule of interest, to wit, adenovirus, into isolated B cells, the method comprising the step of activating endogenous AICD in the B cells for 2 days with LPS prior to transduction (e.g. pg 944, col. 2, Methods, primary B cells).
Mayo et al (Characterization of LPS and interferon-c triggered activation-induced cell death in N9 and primary microglial cells: induction of the mitochondrial gateway by nitric oxide, Cell Death and Differentiation 14: 183-195, 2007) is considered relevant prior art for having taught that LPS inherently and naturally activates AICD (e.g. pg 183, col. 1, topic para).
Similarly, Esser et al (Rapid induction of transcription of unrearranged witch regions in activated murine B cells by interleukin 4, The EMBO Journal 8(2): 483-488, 1989) is considered relevant prior art for having taught that that LPS stimulation naturally activates class switching in B cells (e.g. pg 483, col. 1, Introduction, “B cells stimulated with LPS preferentially switch from IgM to IgG3”).
Neither McMahon et al nor Li et al teach wherein the artisan’s DNA molecule of interest, to wit, plasmids, are introduced into a switch region of an immunoglobulin gene locus of the B lymphocytes. Rather, the method only results in transient transfection (e.g. pg 255, col. 2), as the thus-introduced plasmids are not integrated into the host cell genome.
Thus, McMahon et al and Li et al would appear to evidence that the instant method recited at a high level of generality does not work as claimed.
Stanic et al (IL-10–overexpressing B cells regulate innate and adaptive immune responses, J. Allergy Clin. Immunol. 135:771-780, 2015) is considered relevant prior art for having taught a method of introducing the artisan’s DNA molecule of interest, to wit, plasmids, into isolated B cells, the method comprising the step of activating the B cells for 3 days with 1uM synthetic TLR9 oligonucleotide prior to transfection (e.g. pg 780.e1, col. 1, Methods, Transfection of B cells).
He et al (CpG DNA Induces IgG Class Switch DNA Recombination by Activating Human B Cells through an Innate Pathway That Requires TLR9 and Cooperates with IL-10, J. Immunol. 173(7): 4479-4491, 2004) is considered relevant prior art for having taught that TLR signals B cell activation, proliferation, and IgM production (Abstract), and CpG DNA inherently and naturally initiates germline constant gene transcription, which is associated with up-regulation of AICD (Abstract; pg 4482, col. 2, “CpG DNA… up-regulate AID (syn. AICD)).
Instant specification also discloses that CpG-B DNA TLR agonists (like Stanic et al) are an embodiment of an AICD activator (e.g. pg 86, lines 8-9).
Simchoni et al (TLR7- and TLR9-Responsive Human B Cells Share Phenotypic and Genetic Characteristics, J. Immunol. 194: 3035-3044, 2015) is considered relevant prior art for having taught that TLR9 agonists, e.g. CpG-B agonist ODN2006, as per He et al, (pg 3036, col. 1) stimulate class switch DNA recombination in B cells, being more likely to have undergone somatic hypermutation (e.g pg 3035, col. 2), as such is expected to appear because activation-induced cytosine deaminase, the enzyme mediating somatic hypermutation, induces mutations whenever the Ig locus is transcribed (e.g. pg 3036, col. 2). Further, TLR9 stimulation skews responding B cells toward IgM expression rather than IgG expression (syn. class switching) (e.g. Figure 3).
Stanic et al do not teach wherein the artisan’s DNA molecule of interest, to wit, plasmids, are introduced into a switch region of an immunoglobulin gene locus of the B lymphocytes. Rather, the method only results in transient transfection, as the thus-introduced plasmids are not integrated into the host cell genome.
Thus, Stanic et al would appear to evidence that the instant method recited at a high level of generality does not work as claimed.
The claims fail to recite, and the specification fails to disclose, how to narrow the target site specificity of the heterologous DNA molecule insertion site to only the switch region of an immunoglobulin locus, to the exclusion of the widespread genomic double-stranded breaks naturally caused by AICD.
Those of ordinary skill in the art would immediately recognize that it is axiomatic that Applicant simply does not possess the enormously vast genus of method step parameters for the broadly claimed DNA molecules to be introduced into the B lymphocytes, their corresponding concentration(s), and the enormous genus of structurally and functionally distinct agents that are to activate endogenous AICD, and their corresponding concentration(s) and temporal parameter(s) so as to necessarily and predictably achieve introduction of the broadly claimed genus of DNA molecule into a switch region of an immunoglobulin gene locus.
While the working examples disclose the use of IL-4 at a concentration of 16ng/ml (e.g. pg 108, line 31, Example 1), the specification fails to disclose working examples of the other 15 cytokine species recited in the Markush Group used in amount as little as 0.01ng/ml, nor as much as 20ng/ml, respectively, in a method of editing the genome of an isolated B cell, thereby necessarily and predictably introducing a heterologous DNA molecule of interest into a switch region of an immunoglobulin gene locus of said B cell.
The instant portion of the invention, as claimed, falls under the "germ of an idea" concept defined by the CAFC. The court has stated that "patent protection is granted in return for an enabling disclosure, not for vague intimations of general ideas that may or may not be workable". The court continues to say that "tossing out the mere germ of an idea does not constitute an enabling disclosure" and that "the specification, not knowledge in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement". (See Genentech Inc v. Novo Nordisk A/S 42 USPQ2d 1001, at 1005). The broadly claimed method comprising the enormous genus of structurally and functionally distinct agents that are to activate endogenous AICD, and their corresponding concentration(s) and temporal parameter(s), and the broadly claimed DNA molecules to be introduced into the B lymphocytes, their corresponding concentration(s), so as to achieve introduction of the broadly claimed genus of DNA molecule into a switch region of an immunoglobulin gene locus constitutes such a "germ of an idea".
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)
Response to Arguments
Applicant argues that AICD activity predominantly targets the switch region of an immunoglobulin locus, as supported by references cited in the IDS.
Applicant’s argument(s) has been fully considered, but is not persuasive. The Examiner has not argued that AICD activity does not target the switch region of an immunoglobulin locus. Rather, the art recognizes (e.g. Hasham et al, Staszewski et al) that AICD activity induces genome-wide double-stranded breaks.
The claims fail to recite how the thus-introduced DNA molecule is to integrate into the immunoglobulin switch region, as opposed to all the other AICD-induced DNA breaks dispersed across the B cell genome, thereby necessarily and predictably achieving the claimed functional result of “into a switch region of an immunoglobulin gene locus”.
The above-cited prior art (e.g. Frecha et al, King et al, Buschle et al, McMahon et al, Stanic et al) evidence that mere activation of AICD alone is not sufficient to achieve the claimed functional result of “into a switch region of an immunoglobulin gene locus”, as the introduced DNA molecules, e.g. plasmids, remain episomal, not integrated into the B cell genome. Thus, the broadly recited method does not appear to work as claimed.
Figure 1 of instant application illustrates the presence of 5’ and 3’ homology regions flanking the donor sequence to be inserted into the switch region. However, instant independent claim fails to recite the presence of such structures that would be specific for the immunoglobulin switch region.
Claim Rejections - 35 USC § 102
12. The prior rejection of Claim(s) 1, 3, 19-20, 24-25, and 27 under 35 U.S.C. 102(a)(1) as being anticipated by Frecha et al (Efficient and stable transduction of resting B lymphocytes and primary chronic lymphocyte leukemia cells using measles virus gp displaying lentiviral vectors, Blood 114(15): 3173-3180, 2009; of record) is withdrawn in light of Applicant’s amendment to the independent claim, introducing new cytokine concentrations and restimulating steps, which Frecha et al do not teach.
13. The prior rejection of Claim(s) 1, 3, and 19-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by King et al (U.S. 2013/0102031) is withdrawn in light of Applicant’s amendment to the independent claim, introducing new cytokine concentrations and restimulating steps, which King et al do not disclose.
Conclusion
14. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638