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 .
Applicant’s amendments to the claims dated 7/31/24 are acknowledged. Claims 1-75 are cancelled. Claims 76-95 are new. Prosecution on the merits commences for claims 76-95.
PRIORITY
The instant application, filed 4/12/2024, is a DIVISIONAL of US Patent No. 12,004,495, filed 09/02/2020; which is a CONTINUATION of PCT/CN2020/075698, filed 02/18/2020; which claims priority to PCTCN2019106320, filed 09/18/2019; and PCTCN2019075406, filed 02/18/2019. Thus, the earliest possible priority for the instant application is 02/18/2019.
Drawings
The drawings of record 4/12/2024 are objected to because they do not conform with requirements of 37 CFR 1.84, sections (g) and (p).
(g) requires a top margin of at least 2.5 cm. (1 inch), a left side margin of at least 2.5 cm. (1 inch),
a right side margin of at least 1.5 cm. (5/8 inch), and a bottom margin of at least 1.0 cm. (3/8 inch); and
(p) requires the text be plains, legible and comprehensible.
The margins of FIGs. 26, 28, 41-44, 59, and 71A are smaller than allowed by 37 CFR 1.84 (g).
Various text sections of the graphs within FIGs. 45-50 are blacked out (Legend, y-axis, x-axis, etc.).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
PRODUCT-BY-PROCESS CLAIMS, MPEP 2113.
Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps.
CLAIMS
Independent claims 76, 90 and 93 are drawn to a genetically modified rodent produced by a process of targeted recombination, wherein the process comprises, at least, introducing two different recombination sites in a human chromosome, introducing two different recombination sites in an endogenous rodent chromosome, inducing site specific recombination between the human chromosome and the rodent chromosome, thereby replacing the endogenous rodent sequence with the exogenous sequence from the human chromosome, wherein the process integrates at least 500 kb in one recombination step.
PNG
media_image1.png
200
400
media_image1.png
Greyscale
Claims 76, 90 and 93 are presented below:
Claims 90 and 93 define the location of the insertion(s) in the rodent chromosome, and the human sequence(s) that are inserted. However, the general structure of the rodent claimed in the product-by-processes comprise the replacement of endogenous rodent sequences of at least 500 kb with 500 kb of human sequences. Thus, as written, the final genomic structure (ignoring the specific location/insertion sites of claims 90 and 93) produced from 1) a single step with one insert; 2) a single step comprising multiple overlapping inserts; or 3) from a process of multiple steps are identical.
PNG
media_image2.png
443
696
media_image2.png
Greyscale
Thus, the broadest reasonable interpretation of claim 76 is a genetically modified rodent, wherein at least 500 kb of endogenous rodent sequences have been replaced with at least 500 kb of human sequences;
claim 90 further requires wherein the at least 500 kb of human sequences comprise at least human IGHV(III)-82, IGHV7-81, IGHV4-80, IGHV3-79, IGHV(II)-78-1, IGHV5-78, IGHV7- 77, IGHV(III)-76-1, IGHV3-76, IGHV3-75, and IGHV(II)-74-1; and
claim 93 further requires wherein the at least 500 kb human sequence:
1) comprise at least human IGHV(III)-82, IGHV7-81, IGHV4-80, IGHV3-79, IGHV(II)-78-1, IGHV5-78, IGHV7- 77, IGHV(III)-76-1, IGHV3-76, IGHV3-75, and IGHV(II)-74-1; and
2) is operably linked to one or more of endogenous IGHM, IGHδ, IGHG, IGHE, and IGHA genes.
Claim Objections
Claims 93-95 are objected to because of the following informalities:
Independent claim 93 is drawn to a “genetically-modified rodent” produced by a method comprising, at least, modifying and replacing a “mouse” chromosome with a human chromosome sequence. While all mice are rodents, not all rodents are mice. It would be remedial to amend claim 93 to recite a “genetically-modified
Claims 94 and 95 are objected to because they are each directed to “the rodent of claim 93” and should be amended to recite, at least, “The genetically-modified mouse of claim 93” for consistency.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) - indefinite
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 76-95 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 76, directed to “a genetically-modified rodent prepared by” requires, at least, a method of
(a) modifying a human chromosome with a first and second recombination site, wherein the first and second recombination sites are different;
(b) modifying an endogenous rodent chromosome with a first and second recombination site, wherein the first and second recombination sites are different;
(c) introducing the modified human chromosome into a cell of the rodent; and
(d) inducing site specific recombination between the modified human chromosome and an endogenous chromosome, thereby replacing a sequence at the endogenous chromosome with a sequence from the modified human chromosome...”
It is unclear whether the “an endogenous chromosome” of step (d) is referring back to the modified endogenous chromosome produced in step (b), or if the step (d) is referring to a different (i.e. unmodified) endogenous rodent chromosome? It is unclear what endogenous rodent chromosome the modified human chromosome is being integrated into?
Claim 76 is further indefinite. The preamble, encompassing a genetically-modified rodent “prepared by” raises the question of whether the process steps of (a)-(d) are performed on:
1) a non-genetically modified rodent, such that the process steps are the steps that “prepare” (i.e. result in) the genetically-modified rodent? Or
2) an already genetically-modified rodent, and the process steps are further genetic modifications?
In addition, the Examiner notes that although process steps (a)-(d) of claim 76 structurally result in the replacement of an endogenous chromosomal sequence (necessarily a deletion and disruption) in a rodent cell by the integration of a sequence from the modified human chromosome, such structure as claimed does not aid in resolving the lack of clarity in the claim. It is not clear at what point in the claim and/or claimed product-by-process, wherein a skilled artisan can differentiate “a rodent” from “a genetically-modified rodent” from “a genetically-modified rodent prepared by” from “wherein the replacement of the endogenous chromosomal sequence with the integrated modified human chromosome results in a/the genetically-modified rodent”?
Independent claims 90 and 93, are also directed to “a genetically-modified rodent prepared by” and are indefinite for the same reasons as stated above for independent claim 76. It is not clear at what point in the claims and/or claimed products-by-processes, wherein a skilled artisan can differentiate “a rodent” from “a genetically-modified rodent” from “a genetically-modified rodent prepared by” from “wherein the replacement of the endogenous chromosomal sequence with the integrated modified human chromosome results in a/the genetically-modified rodent”?
The confusion regarding claim 76 permeates through dependent claims 77-89.
Claim 77 requires wherein “the rodent comprises a disruption in the rodent’s endogenous heavy chain immunoglobulin gene locus.” It is unclear whether “the rodent” comprising “a disruption” in claim 77 refers to the genetically-modified rodent prepared the modifications of claim 76? And if so, does the replacement and integration of the endogenous chromosomal sequence of claim 76 result in the “a disruption” of the rodent’s endogenous heavy chain immunoglobulin gene locus encompassed by claim 77?
Or, does “the rodent” comprising “a disruption” in claim 77 refer to a rodent before the modifications of claim 76? If so, the rodent comprising the “a disruption” of claim 77 is necessarily already a genetically-modified rodent, and it is unclear how to differentiate “a/the rodent” from “a/the genetically-modified rodent.”
Claim 78, dependent upon claim 77, states, “wherein the rodent is a mouse and the disruption in the endogenous heavy chain immunoglobulin gene locus comprises…” This claim is indefinite for the same reasons as stated above for claim 77.
Claim 79, dependent upon claim 76, recites “the rodent” which encompasses the “the integrated human sequence” at "the endogenous heavy chain immunoglobulin gene locus" in line 2. There is insufficient antecedent basis for "the endogenous heavy chain immunoglobulin gene locus" in line 2.
However, claim 79 is also indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 76 or in claim 79.
Claim 80, dependent upon claim 76, recites, “the rodent” comprises “human … [immunoglobulin heavy chain variable genes]…at the endogenous heavy chain immunoglobulin gene locus.” There is insufficient antecedent basis for "the endogenous heavy chain immunoglobulin gene locus" in line 3.
However, claim 80 is also indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 76 or claim 80.
Claim 81, dependent upon claim 76, recites, “the rodent” expresses specific human immunoglobulin heavy chain variable genes; thus “the rodent” of claim 81 is necessarily a genetically- modified rodent. Claim 81 is indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 76 or claim 81.
Claim 82, dependent upon claim 76, recites, “the rodent” comprises (1) at least 150 human immunoglobulin heavy chain variable genes are “integrated into the endogenous chromosome by recombination;” (2) at least 20 human immunoglobulin heavy chain D genes are “integrated into the endogenous chromosome by recombination; and (3) at least 5 human immunoglobulin heavy chain J genes are “integrated into the endogenous chromosome by recombination. However, claim 82 is also indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 76 or claim 82. The issue is compounded because the human sequences of claim 82 are not necessarily “the sequence from the modified human chromosome integrated into the endogenous chromosome” comprise at least human immunoglobulin genes of (1), (2) and (3); nor is the integration by “recombination” of claim 82 necessarily the “site-specific recombination” performed in claim 76.
Claim 83, dependent upon claim 76, recites, “the rodent” comprises “at the endogenous heavy chain immunoglobulin gene locus” two different recombination sites, wherein “the integrated human sequence” is between the two recombination sites. There is insufficient antecedent basis for "the endogenous heavy chain immunoglobulin gene locus" in lines 1-2. However, claim 83 is also indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 76 or claim 83.
Claim 84 requires wherein “the rodent comprises a disruption in the rodent’s endogenous light chain immunoglobulin gene locus.” It is unclear whether “the rodent” comprising “a disruption” in claim 84 refers to the genetically-modified rodent prepared the modifications of claim 76? And if so, does the replacement and integration of the endogenous chromosomal sequence of claim 76 result in the “a disruption” of the rodent’s endogenous light chain immunoglobulin gene locus encompassed by claim 84?
Or, does “the rodent” comprising “a disruption” in claim 84 refer to a rodent before the modifications of claim 76? If so, the rodent comprising the “a disruption” of claim 84 is necessarily already a genetically-modified rodent, and it is unclear how to differentiate “a/the rodent” from “a/the genetically-modified rodent” in claim 76 or claim 84.
Claim 85, dependent upon claim 76, recites, “the rodent” further comprises “at an endogenous light chain immunoglobulin gene locus” one or more human light chain variable genes and human light chain joining genes. The recitation of “further comprises” does not make clear that the site-specific process of claim 76 results in the integrated one or more human light chain variable or joining genes, nor does claim 85 require the human light chain immunoglobulin genes are integrated, and replace, the rodent endogenous light chain genes. Thus, claim 85 is indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 76 or claim 85.
Claim 86, dependent upon claim 85, is indefinite for the same reasons as stated for claim 85.
Claims 87, 88, and 89 encompass “the rodent” of claim 76 can produce a humanized antibody; an offspring of “the rodent” of claim 76; and a cell obtained from “the rodent” of claim 76, respectively. Claims 87-89 are indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 76 or claims 87-89.
Independent claim 90, is indefinite for the reasons stated above. Claim 90 is drawn to a genetically modified rodent “prepared by” a method wherein human immunoglobulin heavy chain variable genes are integrated into, and replace endogenous rodent immunoglobulin heavy chain genes by site specific recombination, wherein the human immunoglobulin heavy chain genes comprise at least, IGHV(III)-82, IGHV7-81, IGHV4-80, IGHV3-79, IGHV(II)-78-1, IGHV5-78, IGHV7- 77, IGHV(III)-76-1, IGHV3-76, IGHV3-75, and IGHV(II)-74-1.
Claim 91, dependent upon independent claim 90, recites, “the rodent” expresses specific human immunoglobulin heavy chain variable genes. The claim does not make clear that the specific human immunoglobulin heavy chain variable genes of claim 91 are encoded on, and thus expressed from, the human sequence encoding heavy chain variable genes that is integrated in claim 90. The specific human immunoglobulin heavy chain variable genes expressed from “the rodent” of claim 91 are not those recited as the specific human heavy chain variable genes of claim 90. And “the rodent” of claim 91, expressing specific human immunoglobulin heavy chain variable genes, is necessarily a genetically-modified rodent. Thus, claim 91 is indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 90 or claim 91.
Claim 92 encompasses “the rodent” of claim 90, wherein the rodent produces a humanized antibody. Claim 92 is indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 90 or claim 92.
Independent claim 93, is indefinite for the reasons stated above. Claim 93 is drawn to a genetically modified rodent “prepared by” a method wherein human immunoglobulin heavy chain variable genes are integrated into, and replace endogenous mouse immunoglobulin heavy chain genes from mouse IGHV1-85 to mouse IGHJ4 by site specific recombination, wherein the human immunoglobulin heavy chain genes comprise at least, IGHV(III)-82, IGHV7-81, IGHV4-80, IGHV3-79, IGHV(II)-78-1, IGHV5-78, IGHV7- 77, IGHV(III)-76-1, IGHV3-76, IGHV3-75, and IGHV(II)-74-1.
Claim 94, dependent upon independent claim 93, recites, “the rodent” expresses specific human immunoglobulin heavy chain variable genes. The claim does not make clear that the specific human immunoglobulin heavy chain variable genes of claim 94 are encoded on, and thus expressed from, the human sequence encoding heavy chain variable genes in claim 93. The specific human immunoglobulin heavy chain variable genes expressed from “the rodent” of claim 93 are not those recited as the specific human heavy chain variable genes of claim 94. There is no requirement, in the claims or specification, that a specific rodent gene is replaced with its specific orthologous human gene. And “the rodent” of claim 94, expressing specific human immunoglobulin heavy chain variable genes, is necessarily a genetically- modified rodent. Thus, claim 94 is indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 93 or claim 94.
Claim 95 encompasses “the rodent” of claim 93, wherein the rodent produces a humanized antibody. Claim 95 is indefinite for the reasons stated above, because it is not clear how to differentiate “a/the rodent” from “a/the genetically-modified rodent”, and what genetic modifications are encompassed by “a/the genetically modified rodent” in claim 93 or claim 95.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 76-77, 79, 84-85, and 87-89 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US Patent Application Publication No. 2014/0033336 to Murphy, of record, IDS 4/12/24.
With regard to claim 76, Murphy discloses generating transgenic mice comprising replacing the entire mouse heavy chain V, D and J genomic locus with the orthologous human heavy chain V, D and J genomic locus, using homologous recombination, such that the human V, D, and J locus is operably linked to the endogenous constant region (paragraphs [0017]-[0019], [0023], [0024], [0026]; FIGS 4A-D; Example 3; paragraph [0081]).
Murphy discloses the endogenous heavy chain immunoglobulin locus is disrupted by the direct in situ replacement of the mouse sequences with the entire human VDJ genomic transgene (Example 3). Murphy teaches that the endogenous mouse heavy chain VDJ region, from 5’ to 3’ is deleted, when the orthologous human heavy chain VDJ region sequences are inserted (See paragraphs [0016]-[0018], [0024], [0026], FIGs 4A-4D). Murphy shows that the whole human heavy chain locus is at least 500 kb of contiguous human sequences at figure 4A:
PNG
media_image3.png
172
910
media_image3.png
Greyscale
Thus, Murphy discloses a genetically modified rodent, wherein at least 500 kb of endogenous rodent sequences have been replaced with at least 500 kb of human sequences.
With regard to claim 77, Murphy discloses the endogenous heavy chain immunoglobulin locus is disrupted by the direct in situ replacement of the mouse sequences with the entire human VDJ heavy chain genomic transgenes (Example 3).
With regard to claim 79, Murphy discloses the mouse is homozygous for the modified locus (paragraph [0095]).
With regard to claims 84-85, Murphy discloses the endogenous light chain immunoglobulin locus is disrupted by the direct in situ replacement of the mouse sequences with one or more human light chain IGKV or IGKJ genomic transgenes (Example 3, paragraphs [0086]), [0095].
With regard to claim 87, Murphy discloses the mouse can produce an antibody comprising segments encoded by the human gene segments (Example 3).
With regard to claim 88, Murphy discloses the mouse can produce offspring (Example 3; paragraphs [0092]-[0095])
Regarding claim 89, Murphy discloses cells obtained from the non-human mouse (paragraphs [0090]-[0095], Example 3).
Claims 76-77, 79, 84-85, 87-89 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Murphy et. al., Mice with Megabase Humanization of Their Immunoglobulin Genes Generate Antibodies as Efficiently as Normal Mice. PNAS, 2014. 111(14): 5153-5158, of record, listed on Applicant’s IDS 4/12/24, herein, “Murphy-2”.
With regard to claim 76, Murphy-2 generates transgenic mice wherein 2.6 MB of the mouse heavy chain V, D and J genomic sequence is replaced with 1 Mb of human heavy chain V, D and J genomic sequence, such that the human V, D, and J sequence is operably linked to the endogenous constant region (Abstract, pages 5154, 5157, FIG 1A, C). The transgenic mice further comprise wherein 3.0 Mb of the mouse light chain K genomic sequence is replaced with 0.5 Mb (580 kb) of human light chain genomic sequence, such that the human light chain locus is operably linked to the endogenous constant region (Abstract, pages 5154, 5157, FIG 1B-C).
Murphy-2 discloses the endogenous heavy chain immunoglobulin locus is disrupted by the replacement of the 2.6 Mb mouse sequences with the 1Mb human VDJ genomic transgene, and the endogenous kappa light chain locus is disrupted by the replacement of the 3 Mb mouse sequences with the 0.5 Mb human K genomic transgene (page 5154, FIG 1A-B). Thus, Murphy-2 discloses a genetically modified rodent, wherein at least 500 kb of endogenous rodent sequences have been replaced with at least 500 kb of human sequences.
With regard to claim 77, Murphy-2 discloses the endogenous heavy chain immunoglobulin locus is disrupted by the direct in situ replacement of the mouse sequences with the human VDJ heavy chain genomic transgenes (page 5154, FIG 1A).
With regard to claim 79, Murphy-2 discloses the mouse is homozygous for the modified locus (page 5154, FIG 1A).
With regard to claims 84-85, Murphy-2 discloses the endogenous light chain immunoglobulin locus is disrupted by the direct in situ replacement of the mouse sequences with one or more human light chain IGKV or IGKJ genomic transgenes (page 5154, FIG 1A).
With regard to claim 87, Murphy-2 discloses the mouse can produce an antibody comprising segments encoded by the human gene segments (pages 5156-5157, FIG 3).
With regard to claim 88, Murphy-2 discloses littermates of the produced mice were immunized, thus showing the mouse can produce offspring (page 5157).
Regarding claim 89, Murphy-2 discloses cells obtained from the non-human mouse (page 5156, Table 1).
Claims 76-77, 79, 84-85, and 87-89 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by MacDonald et. al., Precise and in Situ Genetic Humanization of 6 MB of Mouse Immunoglobulin Genes. PNAS, 2014. 111(14): 5147-5152, of record, IDS 4/12/24.
With regard to claim 76, MacDonald generates three lines of genetically modified transgenic mice wherein:
1) 2.6 MB of the mouse heavy chain V, D and J genomic sequence is replaced “with roughly 1 Mb of contiguous human genomic sequence containing the equivalent human” heavy chain V, D and J genomic sequence (page 5148), such that the human V, D, and J locus is operably linked to the endogenous constant region (Abstract, pages 5147-5149, 5155, FIG 1A-C, Table 1);
2) 3.0 Mb of the mouse light chain K genomic sequence is replaced with 0.5 Mb (580 kb) of human light chain genomic sequence, such that the human light chain locus is operably linked to the endogenous constant region (Abstract, page 5149, FIG 2A-C); and
3) both the 2.6 MB of the mouse heavy chain V, D and J genomic sequence is replaced with 1 Mb of contiguous human heavy chain V, D and J genomic sequence, AND 3.0 Mb of the mouse light chain K genomic sequence is replaced with 0.5 Mb (580 kb) of human light chain genomic sequence (page 5149). Thus, MacDonald discloses a genetically modified rodent, wherein at least 500 kb of endogenous rodent sequences have been replaced with at least 500 kb of human sequences.
With regard to claims 77 and 84-85, MacDonald discloses the endogenous heavy chain immunoglobulin locus is disrupted by the replacement of the 2.6 Mb mouse sequences with the 1Mb human VDJ genomic transgene, and the endogenous kappa light chain locus is disrupted by the replacement of the 3 Mb mouse sequences with the 0.5 Mb human K genomic transgene, including one or more human light chain IGKV or IGKJ genomic transgenes (page 5148-5150, FIG 1A-C, 2A-C).
With regard to claim 79, MacDonald discloses all three mouse models are homozygous for the modified locus (page 5149-5150).
With regard to claim 87, MacDonald discloses the humoral immune systems of the transgenic mice “function as efficiently as those of WT mice” (Abstract) and “have already generated therapeutic candidates that have progressed into human trials” (page 5147, “Significance”). Thus, the mice can produce an antibody comprising segments encoded by the human gene segments.
With regard to claim 88, MacDonald discloses the human heavy chain transgenic mice were crossed with the human light chain transgenic mice, to product mice comprising both human heavy chain and human light chain transgenic mice (page 5150), thus showing the mice comprising a 500 kb replacement of mouse sequence can produce offspring.
Regarding claim 89, MacDonald discloses the presence of the integrated transgenes, and the detection of hetero/homozygocity was confirmed in the mice by southern analysis (page 5149). As such, cells from the mice were obtained from the non-human mouse (page 5149).
Claim Rejections - 35 USC § 103
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 80-82 and 90-95 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2014/0033336 to Murphy, of record, IDS 4/12/24, as applied to claims 76-77, 79, 84-85, and 87-89 above, and further in view of Genbank Accession No. AB019437, of record, IDS 4/12/24, and IMGT Repertoire (IG and TR) Gene Table: Human (Homo sapiens) IGHV, of record, IDS 4/12/24, herein after “the IMGT Repertoire human IGHV Gene Table,” and Green et al. Regulation of B Cell Development by Variable Gene Complexity in Mice Reconstituted with Human Immunoglobulin Yeast Artificial Chromosomes. Journal of Experimental Medicine, 1998. 188(3):483-495, of record, IDS 4/12/24.
Claims 80-82 and 90-95 are directed to genetically modified rodents, including mice, wherein at least 500 kb of endogenous rodent sequences have been replaced with at least 500 kb of human sequences, wherein the claims further delineate the genomic structure of the genetically modified rodent and/or identify functional limitations.
Murphy is applied as in the 102 rejection above, the content of which is incorporated herein in its entirety. Murphy discloses generating genetically modified mice comprising the insertion of at least 500 kb of human sequences, wherein the whole endogenous heavy chain (VDJ) and/or light chain (K) immunoglobulin locus, from 5’ to 3’, is replaced (and deleted) with the human heavy chain and/or light chain gene locus, and wherein the human V, D, and J locus is operably linked to the endogenous constant region, as well as endogenous transcriptional control sequences 5’ and 3’ of the VDJ segments (paragraphs [0017]-[0019], [0023], [0024], [0026], [0081], [0083]-[0084], [0088]; FIGS 4A-D; Example 3). Murphy discloses the sequence of the entire human heavy chain locus region is available in Gen Bank files AB019441, AB0199438, AB019439, AB019440, AB019441, X97051 and X54713 (paragraph [0089]).
Murphy discloses that because the genome comprises entirely human heavy and light chain variable regions operably linked to entirely endogenous mouse constant region genes, at the endogenous location, the mouse produces chimeric antibodies comprising human variable regions and mouse constant regions following the natural process of immunoglobulin gene rearrangements during B-cell development (paragraphs [0026], [0077], [0081], [0083]-[0084]). Thus, the human sequences are operably linked to one or more of endogenous IGHM, IGHδ, IGHG, IGHE, and IGHA genes.
However, Murphy does not show the rodent comprises human IGHV(III)-82, IGHV7- 81, IGHV4-80, IGHV3-79, IGHV(II)-78-1, IGHV5-78, IGHV7-77, IGHV(III)-76-1, IGHV3-76, IGHV3-75, and IGHV(II)-74-1 at the endogenous heavy chain immunoglobulin gene locus, as required by instant claim 80 (dependent upon claim 76), and independent claims 90 and 93.
Genbank Accession No. AB019437 represents the first 200,000 bases of the human heavy chain locus, wherein the first features of the locus are 3-82P (IGHV(III)-82), 7-81 (IGHV7- 81), 4-80 (IGHV4-80), 3-79 (IGHV3-79), 78-1 (IGHV(II)-78-1), 5-78 (IGHV5-78), 76-1 (IGHV(III)-76-1), 3-76 (IGHV3-76), 3-75 (IGHV3-75), and 74-1 (IGHV(II)-74-1), see pages 2-3). It is noted that AB019437 does not list 7-77 (IGHV7-77).
The IMGT Repertoire human IGHV Gene Table shows 7-77 (IGHV7-77) is located on chromosome 14 in the human heavy chain variable locus.
Green discloses two early mouse models comprising a human immunoglobulin gene segment capable of undergoing rearrangement, each comprising a human heavy chain variable region, a human D segment and a human J segment (Abstract). Green compared one mouse with a short transgene (5 VH genes and 3 VK genes) compared to a mouse with long transgene (66VH genes and 32VK genes) (abstract, page 484, FIG 1). Green shows that the mouse with the larger insert comprised 5 functional variable genes from the yH1 YAC, and an additional 61 variable genes, 34 functional genes, and 27 pseudogenes (FIG 1 legend, page 484-485). Green shows that the mouse with the larger, more complex variable insert has improved B cell and antibody production compared to the shorter mouse (FIG 2, 4-6, Table 1). Green notes that the native structures of the human transgenes include non-functional/pseudogenes already present in the locus. Green discloses the insertion of the human transgenes into the germline in a “native organization and structure” allows for the ability to study the contribution of the size and complexity of variable chain in vivo (page 491, 494).
Green notes that while the mouse with the larger heavy chain variable insert has improved responses to B cell and antibody production –when compared to the mouse with the shorter insert--, the mouse did not show complete wild-type responses. “The lack of complete reconstitution may stem from specific features of the human antibody repertoire…Positive selection and expansion of the mature B cell population could also be impaired by the absence of specificities, such as those associated with the human Vλ genes” (page 493). As such, Green suggests that the lack of complete wild-type responses may be due to features from the wild type gene(s) that have not been incorporated into the mouse.
Thus, Green establishes that a longer human variable transgene, in a native orientation and structure, comprising pseudogenes therein, has improved properties in vivo than a smaller one. Further, Green suggests that the inability of the larger transgenic mice to completely reconstitute wild-type phenotypes may be due to portions of the human locus that is missing.
With regard to the claimed requirement that the animal comprises human IGV(III)-82, IGHV7-81, IGV4-80, IGHV3-79, IGHV(II)-78-1, IGV5-78, IGHV7-77, IGHV(III)-76-1, IGHV3-76, IGHV3-75, and IGHV(II)-74-1 from human chromosome 14, it would have been obvious to combine the disclosure of Murphy with Genbank Accession No. AB019437, the IMGT Repertoire human IGHV Gene Table, and Green to arrive at the claimed invention. Murphy specifically discloses that the “entire” human heavy chain variable gene can be inserted into the mouse chromosome, and provides the Genbank Accession Numbers which provide the entire locus. Genbank Accession No. AB019437 encodes the distal end of the human heavy chain locus at chromosome 14, and the first listed features are IGHV(III)-82 through IGHV(II)-74-1 and the IMGT Repertoire human IGHV Gene Table comprises IGHV7-77 is therein. The motivation to encode the human heavy chain from IGHV(III)-82 comes from the prior art: Murphy details the process of cloning and inserting the “entire” locus into the mice; further, Green shows that while the larger transgenic mouse had improved phenotypes compared to the shorter transgenic, the phenotypes were not fully wild-type, and suggests the phenotypes were being effects by locus sequences that were not included in the mouse. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention, as the art taught transgenic mice that have the entire human variable gene region, and shows that the more native the transgene is, the better the immune response.
Claims 81, 91 and 94 encompass an embodiment wherein the rodent expresses variable genes IGHV3-15, IGHV3-53, IGHV3- 66, IGHV5-51, IGHV1-24, IGHV1-18, IGHV1-69, IGHV3-7, IGHV3-74, IGHV3-23, IGHV3- 43, IGHV3-21, IGHV3-30-3, IGHV4-59, IGHV6-1, IGHV3-48, IGHV4-34, IGHV4-39, IGHV3- 33, IGHV3-30, IGHV4-61, IGHV3-47, IGHV3-NL1, IGHV3-69-1, IGHV7-4-1, IGHV1-58, IGHV4-28, IGHV2-26, IGHV2-5, IGHV3-64, IGHV3-20, IGHV2-70, IGHV3-11,IGHV4-30-2, IGHV3-13, IGHV3-49, IGHV5-10-1, IGHV3-72, IGHV1-2, IGHV4-30-4, IGHV1-46, IGHV3- 64D, IGHV1-3, IGHV3-73, IGHV4-4, and IGHV4-31.
As noted above, Murphy discloses a genetically modified rodent comprising all human V genes, all human D genes, and all human J genes, inserted at the orthologous mouse immunoglobulin location, and operably linked to endogenous mouse constant regions and endogenous transcriptional control sequences, following the natural process of immunoglobulin gene rearrangements during B-cell development and antibody production. The IMGT Repertoire human IGHV Gene Table is cited to show the claimed human V genes are encoded within human chromosome 14. Thus, Murphy in view of the IMGT Repertoire human IGHV Gene Table render obvious claims 81, 91 and 94.
Claim 82 encompasses an embodiment wherein the animal comprises at least 150 human IgHV genes selected from those listed (representing the known IgHV genes encoded on chromosome 14), at least 20 human IgDH genes selected from those listed (representing the known IgHD genes encoded on human chromosome 14), and at least 5 human IgHJ genes selected from those listed (representing the known IgHJ genes encoded on Human chromosome 14).
Murphy discloses the non-human transgenic animal comprises all human heavy chain VDJ gene segments (FIGS 4A-D; Example 3; paragraph [0081]). Murphy discloses the human heavy chain variable locus can be cloned from known sequences (paragraph [0081]). Genbank Accession No. AB019437 and the IMGT Repertoire human IGH are cited to show the genes identified in claim 82 are encoded on human chromosome 14. Thus, Murphy in view of Genbank Accession No. AB019437 and the IMGT Repertoire human IGH render obvious claim 82.
With regard to claims 92 and 95, Murphy discloses that because the genome comprises entirely human heavy and light chain variable regions operably linked to entirely endogenous mouse constant region genes, at the endogenous location, the mouse produces chimeric antibodies comprising human variable regions and mouse constant regions following the natural process of immunoglobulin gene rearrangements during B-cell development (paragraphs [0026], [0077], [0081], [0083]-[0084]). Thus, Murphy discloses the genetically modified mice produce humanized antibodies.
Claim 78 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2014/0033336 to Murphy, of record, IDS 4/12/24, as applied to claims 76-77, 79, 84-85, and 87-89 above, and further in view of IMGT Repertoire (IG and TR) Gene Positions: IGH Mouse (Mus musculus) C57BL/6J in GRCm38.93 assembly, hereinafter “the IMGT Repertoire Mouse IGH” of record, IDS 4/12/24.
Claim 78 is directed wherein the deletion of the entire endogenous VDJ region of the mouse comprises IGHV1-85 gene to mouse IGHJ4 gene.
Murphy is applied as in the 102 rejection above, the content of which is incorporated herein in its entirety. Murphy discloses generating genetically modified mice comprising the insertion of at least 500 kb of human sequences, wherein the whole endogenous heavy chain (VDJ) and/or light chain (K) immunoglobulin locus, from 5’ to 3’, is replaced (and deleted) with the human heavy chain and/or light chain gene locus, and wherein the human V, D, and J locus is operably linked to the endogenous constant region, as well as endogenous transcriptional control sequences 5’ and 3’ of the VDJ segments (paragraphs [0017]-[0019], [0023], [0024], [0026], [0081], [0083]-[0084], [0088]; FIGS 4A-D; Example 3).
However, Murphy does not identify the contiguous deletion of the entire mouse VDJ region, as shown in FIG. 4B, is from mouse “IGHV1-85 gene to mouse IGHJ4 gene” as required by claim 78.
The IMGT Repertoire Mouse IGH charts the mouse IGH genes linearly along the chromosome. The IMGT Repertoire Mouse IGH shows the mouse IGHV1-85 is at the 5’ end of the mouse IGH locus – the 2nd most 5’ gene- (page 1), and the mouse IGHJ4 gene is the 3’ most mouse J gene in the locus, upstream of the constant region genes (page 7).
It would have been obvious to combine the disclosure of Murphy with the IMGT Repertoire Mouse IGH to arrive at the claimed invention. It would have been obvious to the skilled artisan to delete, via replacement, the mouse chromosome from mouse IGHV1-85 to the IGHJ4 gene, as these genes represent the boundaries of the endogenous chromosome Murphy discloses as being replaced by the orthologous human heavy chain VDJ region. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as the 5’ and 3’ genes of the murine heavy chain VDJ locus were known at the time of the invention.
Claim 83 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2014/0033336 to Murphy, of record, IDS 4/12/24, as applied to claims 76-77, 79, 84-85, and 87-89 above, and further in view of US Patent Application No.2010/0122361 to Smith, of record, IDS 4/12/24.
Claim 83 encompasses an embodiment wherein heavy chain immunoglobulin gene locus comprises one short flippase recognition target (FRT) site and one loxP recognition sequence, wherein the integrated human sequence is between the FRT site and the loxP recognition sequence.
Murphy is applied as in the 102 rejection above, the content of which is incorporated herein in its entirety. Murphy discloses generating genetically modified mice comprising the insertion of at least 500 kb of human sequences, wherein the whole endogenous heavy chain (VDJ) and/or light chain (K) immunoglobulin locus, from 5’ to 3’, is replaced (and deleted) with the human heavy chain and/or light chain gene locus, and wherein the human V, D, and J locus is operably linked to the endogenous constant region, as well as endogenous transcriptional control sequences 5’ and 3’ of the VDJ segments (paragraphs [0017]-[0019], [0023], [0024], [0026], [0081], [0083]-[0084], [0088]; FIGS 4A-D; Example 3).
Murphy discloses the endogenous chromosome comprises two or more exogenous heterotypic recombination sites in order to control insertion and orientation of recombination (paragraphs [0031], [0052], [0069], [0090]-[0094]). Murphy discloses the recombinase sites can be loxP or FRT sites (paragraph [0052]). However, Murphy does not disclose wherein the integrated human sequence is between a FRT site and a loxP recognition sequence.
Smith discloses methods of generating transgenic non-human animals using recombinase-mediated genomic replacement (RMGR) to replace a large portion of a host animal’s genome with the equivalent orthologous portion of a different animal, including the humanization of mice using orthologous human genomic donor segments (Abstract, paragraphs [0006], [0014]-[0015], [0018]-[0022]). Smith discloses the method comprises inserting two-site specific recombinase sites, such as loxP sites, flanking a portion of an endogenous mouse chromosome that is to be replaced in a mouse ES cell (paragraphs [0021], [0055]-[0056], Examples). Smith discloses the method further comprises generating a vector encoding the human genomic donor segment by inserting the same two site-specific recombinase sites flanking the human genomic donor segment (paragraphs [0036]). Smith discloses the vector encoding the human genomic donor segment is introduced into the modified mouse ES cells, wherein recombination is induced by the expression of a recombinase, resulting in the replacement of the endogenous mouse chromosome segment with the human genomic donor segment in one recombination step (paragraphs [0024]-[0027], [0039]-[0045]; FIGs 4a-c). Smith discloses the modified ES cells are used to generate transgenic animals which express the sequences derived from the human genomic donor segments (paragraphs [0028]-[0034], [0045]-[0052]).
Smith discloses marker genes encoded on an integrated BAC can be flanked with FRT recombinase sites -thus distinct from the loxP sites at the 5’ and 3’ end of the BAC and used to integrate the BAC into the genome-- such that after integration of the BAC into the target chromosome using cre recombinase, an additional recombination event using flippase can occur to excise the marker genes from the genome, thus removing a large amount of extraneous nucleic acid in the mice (paragraph [0051]). Following a replacement event, first using Cre, then flippase results wherein the inserted genes are flanked by a FRT site and a loxP site (paragraph [0097]; FIG 5A-C).
It would have been obvious to combine the disclosure of Murphy with Smith. A skilled artisan would have been motivated to remove marker genes integrated into the recipient genome in order to reduce extraneous nucleic acids in the mice, as taught by Smith. It is prima facie obvious to combining prior art elements according to known methods to yield predictable results (MPEP 2143(A)(I)). In the instant case, the prior art included each element claimed, and that in combination, each element merely performs the same function as it does separately. Murphy is clear the mice can be generated using Cre-lox systems or Flippase-Frt systems, and Smith discloses removable of extraneous marker sequences that are integrated into the genome following Cre recombinase, can be excised using Flippase-FRT sites, and following such removal, the remaining integrated sites have the claimed structure. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as using both Cre-Lox and Flippase-FRT systems to generate site-specific transgenic mice was known in the art at the time of the invention.
Claim 86 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication No. 2014/0033336 to Murphy, of record, IDS 4/12/24 as applied to claims 76-77, 79, 84-85, and 87-89 above, and further in view of IMGT Repertoire (IG and TR) Gene Table: Human (Homo sapiens) IGKV, hereinafter “the IMGT Repertoire IGKV,” of record, IDS 4/12/24.
Claim 86 encompasses an embodiment wherein the rodent expresses a variety of KV light chain genes.
Murphy is applied as in the 102 rejection above, the content of which is incorporated herein in its entirety. Murphy discloses generating genetically modified mice comprising the insertion of at least 500 kb of human sequences, wherein the whole endogenous heavy chain (VDJ) and/or light chain (K) immunoglobulin locus, from 5’ to 3’, is replaced (and deleted) with the human heavy chain and/or light chain gene locus at their orthologous mouse loci (paragraphs [0016]-[0019], [0023], [0024], [0026], [0081], [0083]-[0084], [0086], [0088], [0095]; FIGS 4A-D; Example 3). Murphy discloses such transgenic mice will have a genome comprising entirely human heavy and light chain variable gene loci operably linked to entirely endogenous mouse constant region such that the mice produce a serum containing an antibody comprising a human variable region and a mouse constant region in response to antigenic stimulation (paragraph [0095]).
However, Murphy does not disclose the specific KV light chains recited within claim 86.
The IMGT Repertoire IGKV reference shows all of the light chain genes encoded on the human light chain locus within chromosome 2.
It would have been obvious to the skilled artisan to encode and express the claimed light chain genes in the transgenic mouse. A skilled artisan would have looked to the known genes encoded on the human light chain locus when generating a transgenic animal encoding “the entire” human immunoglobulin gene, as taught by Murphy. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as the claimed human light chains genes were known at the time of the invention.
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.
Claims 76-95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,004,495. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious variants of the patented claims.
The instant application is a CONTINUATION of U.S. Patent No. 12,004,495.
Independent claim 1 of the ‘495 Patent is drawn to a genetically modified rodent, comprising a 500 kb human sequence comprising contiguous human heavy chain V, D, J genes integrated into the endogenous V, D, J locus by recombination, are operably linked, and can undergo VDJ rearrangement, wherein the modification can be detected by using PCR primer pairs selected from the group consisting of (a) SEQ ID NOs. 13 and 14, (b) SEQ ID NOs. 15 and 16, (c) SEQ ID NOs. 17 and 18, (d) SEQ ID NOs. 19 and 20, (e) SEQ ID NOs. 21 and 22, (f) SEQ ID NOs. 23 and 24, and (g) SEQ ID NOs. 25 and 26.
Instant claims 76, 90 and 93 are anticipated by claim 1 of the ‘495 patent, being drawn to a genetically modified rodent, comprising a 500 kb human sequence comprising contiguous human sequences, including heavy chain V, D, J genes, integrated into the endogenous orthologous locus, including the rodent V, D, J locus.
It would have been obvious to broaden the scope of the patented claims to not require a specific location for the integration, or to remove the requirement wherein the integrated immunoglobin genes within the endogenous rodent genome could be identified by specific sequences.
Instant claims 77-89, 91-92 and 94-95 are obvious variants of, or similar in scope to patented claims 2-22.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY A ARON whose telephone number is (571)272-2789. The examiner can normally be reached Monday-Friday 9AM-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KAA
/CHRISTOPHER M BABIC/ Supervisory Patent Examiner, Art Unit 1633
Prosecution Insights