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 .
Status of the Claims
Claims 1 – 6, 8, 11 – 13, 16, 18 – 27, and 29 – 33 were pending. Claims 1, 22, and 23 have been amended, and claim 2 has been canceled. Claims 1, 3 – 6, 8, 11 – 13, 16, 18 – 27, and 29 – 33 are currently pending and are the subject of this Office Action.
REJECTIONS WITHDRAWN
Claim Rejections - 35 USC § 103
Claims 1 – 6, 8, 11 – 13, 16, 18, 20 – 27, and 30 were rejected under 35 U.S.C. 103 as being unpatentable over WILLIAMS (Williams BA, et al. CD16+NK-92 and anti-CD123 monoclonal antibody prolongs survival in primary human acute myeloid leukemia xenografted mice. Haematologica. 2018 Oct;103(10):1720-1729; an IDS reference submitted 05/18/2021) in view of WU (US 2007/0224201 A1, published 09/27/2007; see PTO-892: Notice of References Cited of 02/12/2025).
In view of the claim amendments in the reply of 06/17/2026, this rejection is withdrawn.
Claims 19, 29, 32 – 33 were rejected under 35 U.S.C. 103 as being unpatentable over WILLIAMS in view of WU as applied to claims 1, 3 – 6, 8, 11 – 13, 16, 18, 20, 21, 26, and 27 above, and further in view of MA (US 2018/0187149 A1, published 07/05/2018; see PTO-892 of 02/12/2025).
In view of the claim amendments in the reply of 06/17/2026, this rejection is withdrawn.
Claim 31 was rejected under 35 U.S.C. 103 as being unpatentable over WILLIAMS in view of WU as applied to claims 1 – 6, 8, 11 – 13, 16, 18, 20 – 27, and 30 and further in view of SHADPOUR (Shadpour H, et al. Enrichment and expansion of cells using antibody-coated micropallet arrays. Cytometry A. 2009 Jul;75(7):609-18; see PTO-892 submitted with this Office Action).
In view of the claim amendments in the reply of 06/17/2026, this rejection is withdrawn.
Double Patenting
Claims 1 – 6, 8, 11 – 13, 16, 18 – 27, and 29 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 7, 12 – 16, and 19 - 21 of copending Application No. 17/115,360 (reference application).
In view of the claim amendments in the reply of 06/17/2026, this rejection is withdrawn.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENTS
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.
Claims 1, 3 – 6, 8, 12 – 13, 18 – 27, and 29 – 33 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.
Independent claims 1 and 22 recite a population of modified cells expressing CD 16 (SEQ ID NO:1), wherein: . . . (iii) the population is a monoclonal population. However, the present specification does not disclose “a monoclonal population” of modified cells.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3 – 6, 8, 12 – 13, 18 – 27, and 29 – 33 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.
Independent claims 1 and 22 recite a population of modified cells expressing CD 16 (SEQ ID NO:1), wherein: . . . (iii) the population is a monoclonal population. However, the present specification does not disclose “a monoclonal population” of modified cells. Although the specification discloses clones of cells (for example at TABLE 6 of the specification, p. 36), the term “monoclonal” is only used regarding antibodies. For the purpose of compact prosecution, “monoclonal population” of modified cells are defined as cells derived from a single, original parent cell or defined as a clone of cells.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3 – 6, 8, 11 – 13, 16, 18, 20 – 21, and 24 – 27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CAMPBELL (AU2014280879A1, published 01/22/2015; see PTO-892: Notice of References Cited submitted with this Office Action).
Present independent claim 1 is directed to a population of modified cells expressing CD 16 (SEQ ID NO:1), wherein: (i) the modified cells were derived from cells of an immortalized cytolytic cancer cell line isolated from a non-Hodgkin's lymphoma subject, wherein the cells comprise genomic integration of a nucleic acid encoding CD16, (ii) the modified cells do not express IL-2, (iii) the population is a monoclonal population comprising one or more of the modified cells, and (iv) the expression level of CD 16 does not decrease or decreases no more than 20% when the modified cells are activated as compared to expression level of CD 16 on the modified cells before activation.
According to the present specification, “examples of haNK® cells include IL2 Dependent haNK® cells ("haNK003 cells") and IL2 Dependent haNK® cells the former additionally express recombinant IL-2 and the latter do not. As used herein, the term "NK cells" refer to a) donor derived NK cells, b) NK-92.176V- CD16.ERIL2 cells (i.e., IL2 Independent haNK® cells) and c) NK-92.176V-CD16 cells (i.e., IL2 Dependent haNK® cells)” (p. 10, end of fourth paragraph). Thus, the population of modified cells expressing CD 16 (SEQ ID NO: 1) of the present claims are NK-92.176V-CD16 cells.
CAMPBELL is directed to a natural killer cell, NK-92 modified to express an Fc receptor on the surface of the cell, such as CD 16 (FcγRIII-A), or other Fcγ or Fc receptors. See CAMPBELL at the abstract.
CAMPBELL teaches the CD16 (mutant F176V) sequence of present SEQ ID NO: 1 with 100% identity. CAMPBELL teaches a CD16 sequence identical to present SEQ ID NO: 1 of present claim 1. See Appendix. Furthermore, CAMPBELL teaches that the NK-92 cell line was modified to express the high affinity variant of CD16 and that the modification is F176V. See CAMPBELL at paragraph 04.
CAMPBELL teaches that the disclosed NK-like cell line NK-92 was discovered in the blood of a subject suffering from a non-Hodgkins lymphoma. See CAMPBELL at paragraph 014.
CAMPBELL also teaches vectors (e.g., non-episomal mammalian vectors) that integrate into the genome of a host cell and replicate as part of the host genome and teaches that in general, useful expression vectors are plasmids and viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses). See CAMPBELL at paragraph 058.
CAMPBELL teaches generation of NK-92 cells with a stably integrated CD16- F176V cDNA. See CAMPBELL at paragraphs 0166c-166d.
CAMPBELL teaches that the modified NK-92 cell can be further modified to concurrently express IL-2 (see CAMPBELL at the abstract), and thus the starting, original cells do not express IL-2.
CAMPBELL teaches that the availability of a clonal human NK cell population that expresses a consistent level of CD 16 activity would provide substantial benefit as a standard effector in the evaluation of antibodies for ADCC activity and specificity (see CAMPBELL at paragraph 0042), and thus, it would have been obvious to produce a monoclonal population of cells from the teachings of CAMPBELL.
Therefore, CAMPBELL renders present claim 1 obvious.
Regarding part (iv) of present claim 1, because the structure of CAMPBELL’s cells are similar to the presently claimed population of modified cells, CAMPBELL’s cells would inherently possess the property where the expression level of CD 16 does not decrease or decreases no more than 20% when the modified cells are activated as compared to expression level of CD 16 on the modified cells before activation. Additionally, it is noted that the activation of the modified cells is merely suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of CAMPBELL. The artisan would have been motivated to make and use the population of modified cells of independent claim 1 because CAMPBELL teaches that it would be an advantage to restore CD 16 expression and the ability to act via the ADCC mechanism to NK-92 cells (see CAMPBELL at paragraph 016). Thus, the artisan would have a reasonable expectation of success from the teachings of CAMPBELL.
Regarding claim 3, CAMPBELL teaches cell lines and methods that potentiate and broaden the effective scope of the ADCC response. See CAMPBELL at paragraph 040.
Regarding claim 4, while CAMPBELL does not expressly state that the disclosed modified cells maintain a steady state of cytotoxicity for at least 5 hours from the initiation of the activation, the structure of CAMPBELL’s cells anticipate the population of modified cells of claim 1 with this property and therefore CAMPBELL’s cells would inherently maintain a steady state of cytotoxicity for at least 5 hours from the initiation of the activation.
Regarding claim 5, because CAMPBELL’s cells have the same structural limitations as the population of modified cells of present claim 1, CAMPBELL’s cells would also express higher level of CD 16 than NK cells from a donor.
Regarding claim 6, because CAMPBELL’s cells have the same structural limitations as the population of modified cells of present claim 1, CAMPBELL’s cells would also have the property where the percentage of modified cells that are positive for CD16 decreases no more than 20% after the modified cells are activated as compared to the modified cells before activation.
Regarding claims 8 and 16, according to the present specification, “CD16 is an Fc receptor which recognizes and binds to the Fc portion of an antibody to activate NK cells for the ADCC effector mechanism. Because they lack CD16 receptors, unmodified NK-92® cells are unable to lyse target cells via the ADCC mechanism” (specification at paragraph 0004). CAMPBELL teaches cell lines and methods that potentiate and broaden the effective scope of the ADCC response (see CAMPBELL at paragraph 040), suggesting that the NK-92 cells disclosed by CAMPBELL are activated. When the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable. See MPEP 2113 (III).
Additionally, it is noted that the activation of the modified cells is merely suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
Regarding claims 11 – 13, because CAMPBELL’s cells have the same structural limitations as the population of modified cells of present claim 1, CAMPBELL’s cells would also have the property wherein the CD 16 expression decreases no more than 10% or than 5% as compared to the modified cells before the activation.
Regarding claim 18, CAMPBELL teaches effector to target cell ratio (E:T) = 1:1. See CAMPBELL at paragraph 0149.
Regarding claims 20 – 21, because CAMPBELL’s cells have the same structural limitations as the population of modified cells of present claim 1, CAMPBELL’s cells would also have the properties recited in present claims 20 – 21.
Regarding claims 24 – 26, according to the present specification, kits comprise the provided IL2 Dependent haNK® cells (p. 28). CAMPBELL teaches that the disclosed cells (e.g., modified and unmodified NK-92), polypeptides, and Abs, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions. Such compositions typically comprise the cell, polypeptide, and/or antibody and a pharmaceutically acceptable carrier. Thus, CAMPBELL discloses the kits of claims 24 – 25 and the pharmaceutical composition of claim 26.
Regarding claim 27, CAMPBELL teaches a method of treating a subject, the subject having a tumor, infection or other lesion, the method comprising administering to the subject modified NK-92 cells expressing an Fc receptor comprising CD16 (FcyRIII-A). See CAMPBELL at claim 19.
Claims 11, 19, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over CAMPBELL as applied to claims 1, 3 – 6, 8, 11 – 13, 16, 18, 20 – 21, and 24 – 27 above, and further in view of MA (US 2018/0187149 A1, published 07/05/2018; see PTO-892 of 02/12/2025).
The teachings of CAMPBELL, regarding claim 1 (from which claims 11, 19, and 29 ultimately depend) are discussed above and are fully incorporated here. Although CAMPBELL anticipates the population of modified cells of present claim 1, CAMPBELL does not expressly teach all the limitations of claims 11, 19, and 29. For the purposes of this rejection, claim 11 is interpreted to be a structural limitation.
MA is directed to an engineered cell comprising a first CAR and a second CAR wherein the engineered cell is an NK-92 cell. See MA at claims 1 and 12.
Regarding claim 11, MA teaches the targeting of K562 cells. See MA at paragraph 0032.
Regarding claims 19 and 29, MA discloses that the engineered cell includes an inducible suicide gene (“safety switch”) which greatly increases safety profile and limits on-target or off-tumor toxicities of the compound CARs. The “safety switch” may be an inducible suicide gene, such as, without limiting, caspase 9 gene, thymidine kinase, cytosine deaminase (CD) or cytochrome P450. See paragraph 0134.
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of CAMPBELL and MA. The artisan would have been motivated to make and use the population of modified cells of claims 11, 19, and 29 because CAMPBELL teaches that it would be an advantage to restore CD 16 expression and the ability to act via the ADCC mechanism to NK-92 cells (see CAMPBELL at paragraph 016) and MA teaches modified NK-92 cells with efficacy of elimination of cancer cells (see paragraph 0311). The artisan would have a reasonable expectation of success from the combined teachings of CAMPBELL and MA.
Claims 22 – 23 and 30 – 33 are rejected under 35 U.S.C. 103 as being unpatentable over CAMPBELL in view of MA as applied to claims 1, 3 – 6, 8, 11 – 13, 16, 18 – 21, 24 – 27, and 29, and further in view of SHADPOUR (Shadpour H, et al. Enrichment and expansion of cells using antibody-coated micropallet arrays. Cytometry A. 2009 Jul;75(7):609-18; see PTO-892 of 12/23/2025).
According to the present specification, “V176-CD16 expressing cells were enriched using a purified anti-human CD16 Antibody (BioLegend, catalog #302002) and anti-mouse IgG MicroBeads from Miltenyi (catalog #130-048-401) following manufacturer's instructions.”
SHADPOUR is directed to the use of an antibody that specifically binds a cell surface receptor for the positive selection of specific cells. See SHADPOUR at Abstract: Methods.
Regarding claims 22 and 31, CAMPBELL teaches most of the steps of the method of present claim 22 (see discussion above) and also teaches using limiting dilution for isolating hybridoma at paragraph 0123 and using retroviruses in Examples 1 and 2, paragraphs 0136 - 0142). Furthermore, MA teaches using lentiviral vectors at paragraphs 0113 – 0117 and 0122. However, neither CAMPBELL nor MA expressly teaches (b) enriching for CD16-expressing cells. However, this is a cell-culture steps known in the art as discussed below.
Regarding the sequence of SEQ ID NO: 2, although CAMPBELL does not teach the nucleic acid sequence of SEQ ID NO: 2, the sequence of SEQ ID NO: 2 encodes CAMPBELL’s CD16 polypeptide. See Appendix. It is noted that the courts have found that the disclosure of the polypeptide makes the nucleic acid encoding the protein obvious as the methods of obtaining the nucleic acids are routine in the art and can be obtained with a reasonable expectation of success. See MPEP 2143(E)(Example 3), Ex parte Kubin, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007), and In re Kubin 90 USPQ2d 1417 (U. S. Court of Appeals Fed. Cir. 2009).
Regarding the cell-culturing steps, SHADPOUR teaches that antibody-based pre-enrichment in combination with micropallet-based cell selection will be a valuable tool for isolation and expansion of rare cells from small heterogeneous populations. See SHADPOUR at Abstract: Conclusions. SHADPOUR teaches that positive selection, sorting, and collection of single or small groups of cells from within a heterogeneous population are common and essential procedures in most areas of biomedical research and that many techniques such as limiting dilution have been used successfully for sorting nonadherent cells using both bench-top and microchip platforms. See SHADPOUR at the first paragraph, p. 1. Thus, it would have been obvious to one having ordinary skill in the art to enrich for CD16-expressing cells and plate the enriched cells by limiting dilution as recited in claims 22 and 31 because SHADPOUR teaches that this is common in the art.
Regarding part (ii) of claim 31, CAMPBELL teaches contacting the modified cells comprising CD16 with IL-2. See CAMPBELL at paragraphs 0165 – 0166.
Regarding claim 23, because MA does not teach the infection of vectors with antibiotics, it is assumed that MA’s lentiviral infection is performed without antibiotics.
Regarding claim 30, while neither none of the cited references expressly states that the disclosed methods would result the expression of CD16 on the activated modified cells is no less than 80% of the CD16 expression on the modified cells before the activation, the active steps taught by CAMPBELL, MA, and SHADPOUR render the method of claim 22 that would result in this property obvious and therefore the taught method by CAMPBELL in view of MA and SHADPOUR would result in the expression of CD16 on the activated modified cells to be no less than 80% of the CD16 expression on the modified cells before the activation.
Regarding claims 32 – 33, MA discloses that the engineered cell includes an inducible suicide gene (“safety switch”) which greatly increases safety profile and limits on-target or off-tumor toxicities of the compound CARs. The “safety switch” may be an inducible suicide gene, such as, without limiting, caspase 9 gene, thymidine kinase, cytosine deaminase (CD) or cytochrome P450. See paragraph 0134.
At the effective filing date of the present claims, it would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of CAMPBELL, MA, and SHADPOUR. The artisan would have been motivated to use the method of claim 31 because CAMPBELL teaches that it would be an advantage to restore CD 16 expression and the ability to act via the ADCC mechanism to NK-92 cells (see CAMPBELL at paragraph 016); MA teaches modified NK-92 cells with efficacy of elimination of cancer cells (see MA at paragraph 0311); and SHADPOUR teaches single-cell cloning studies that demonstrated a high cloning efficiency of target cells (see SHADPOUR at the abstract). The artisan would have a reasonable expectation of success from the combined teachings of CAMPBELL, MA, and SHADPOUR.
Response to Arguments
On page 9, second – third paragraphs of the reply of 06/17/2026, Applicant argues “[t]he Office's theory appears to rest on inherency, but inherency cannot be established by mere possibility or probability. A missing claim limitation is not inherent unless it is necessarily present in the prior art. See, e.g., In re Oelrich, 666 F.2d 578, 581 (CCPA 1981); PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186, 1194 to 1195 (Fed. Cir. 2014). In other words, the standard for inherency is certainty, not speculation. Here, the Office acknowledges that Williams does not expressly disclose the CD 16 expression level recited in claim 1. Nevertheless, the Office asserts that ‘the structure of Williams' cells is the same as the structure of the claimed modified cells ... [therefore, the cells] would have the same properties.’ See, Office Action, p. 11. That conclusion is unsupported. The Office identifies no evidence establishing that the structure of Williams' cells is actually the same as that of the presently claimed cells. Nor, as discussed in detail in the previous Office Action response filed November 13, 2025, does the Office provide evidence that the claimed post activation CD16 expression profile necessarily results merely because Williams' cells express CD16 from a transgene.”
Applicant’s arguments are not persuasive because under MPEP 2112.01, when the structure or composition of a prior art reference is identical or substantially identical to a claimed product, any properties or functions not expressly disclosed by the prior art reference are presumed to be inherent. The present claims are directed to a population of modified cells expressing CD 16 (SEQ ID NO:1), wherein: (i) the modified cells were derived from cells of an immortalized cytolytic cancer cell line isolated from a non-Hodgkin's lymphoma subject. The present specification states that the cells of the application are NK-92.176V-CD16, which are NK 92 cells expressing CD16 with an F176V mutation (see the specification at p. 10, fourth paragraph and last paragraph. Furthermore, the claimed SEQ ID NO: 1 consists of the F176V mutation. WILLIAMS teaches that “[s]ince the parental NK-92 cell line lacks CD16, and cannot mediate ADCC, a high-affinity allelic variant (valine at position 176 instead of phenylalanine) of the CD16A Fcγ receptor was transduced into the NK-92 cell line. These gene-modified CD16NK-92 cells (NK-92.176V and NK-92.176V.GFP) demonstrate ADCC in vitro”. See WILLIAMS at p. 1721, left column, second paragraph. Furthermore, WILLIAMS’ cells were not produced by its authors – rather, the “NK-92 and NK-92.176V GFP (hereafter referred to as CD16NK-92) was obtained from Conkwest under a Material Transfer Agreement (MTA)” and therefore, WILLIAMS does not expressly teach the steps that led to the structure of the cells. Nonetheless, evidence from the present specification and WILLIAMS, as discussed above, suggests that the claimed population of cells are identical or substantially identical to WILLIAMS’ NK-92.176V cells. Thus, WILLIAMS’ NK-92.176V cells would also exhibit an expression level of CD 16 that does not decrease or decreases no more than 20% when the modified cells are activated as compared to expression level of CD 16 on the modified cells before activation as recited in present claim 1.
Nonetheless, CAMPBELL has been applied in place of WILLIAMS because CAMPBELL teaches the structural limitations of newly amended claim 1.
On p. 10, last paragraph – p. 11 first paragraph of the reply, Applicant argues that “[a]s shown in Tables 4 and 5 (portions of which are shown below), CD16 expression decreases dramatically in donor-derived NK cells after activation, whether activation is induced by PMA/ionomycin treatment or by co- culture with K562 cells.”
However, TABLES 4 and 5 show expression of CD 16 after activation by PMA/ionomycin and expression of CD16 after activation by contacting K562 cells in donor derived NK cells and IL2 Dependent HaNK® Cells which recombinantly express the CD16 as taught in Campbell, The IL2 Dependent HaNK® Cells do not show a significant reduction in CD16 expression. Thus, the CD16 of Campbell would also not show a significant reduction in CD16 expression. Additionally, as noted above, activation of the modified cells expressing CD16 is an intended use of the cells that does not structurally change the cells.
Furthermore, MPEP 2145 states that "[e]vidence pertaining to secondary considerations must be taken into account whenever it has been properly presented; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007) ('the record establish[ed] such a strong case of obviousness' that allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion); Leapfrog Enterprises Inc. v. Fisher-Price Inc., 485 F.3d 1157, 1162, 82 USPQ2d 1687, 1692 (Fed. Cir. 2007) ("given the strength of the prima facie obviousness showing, the evidence on secondary considerations was inadequate to overcome a final conclusion" of obviousness); and Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988)."
On p. 11, second-to-last and last paragraphs, Applicant argues that “Wu does not remedy these deficiencies in Williams. Wu discloses the CD16 sequence but does not discuss genomic integration of CD16, a monoclonal population of cells that express CD16 from the genome, or the claimed expression profile. Thus, the combination of Williams and Wu does not teach or suggest amended claim 1, and amended claim 1 is not rendered obvious by Williams and Wu” and that “Ma does not remedy the deficiencies of Williams and Wu”.
WU was applied to show that the CD16 sequence of the claimed SEQ ID NO: 1 is known in the art. However, CAMPBELL teaches this sequence as discussed above.
On p. 11, last paragraph of the reply, Applicant argues that MA does not remedy the deficiencies of WILLIAMS and WU. However, WILLIAMS and WU have been replaced with CAMPBELL, and MA has been applied because MA teaches limitations not expressly disclosed in CAMPBELL.
On p. 12 – 13 of the reply, Applicant argues that claim 22 is not obvious in view of the cited art of WILLIAMS, WU, and MA, and/or SHADPOUR. However, WILLIAMS and WU have been replaced with CAMPBELL, MA and SHADPOUR are applied in view of CAMPBELL as discussed in the new rejections above.
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 1, 3 – 6, 8, 11 – 13, 16, 18 – 27, and 29 – 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 7, 12 – 16, and 19 - 21 of copending Application No. 17/115,360 in view of CAMPBELL, MA, and SHADPOUR.
Copending claim 1 recites a method for generating a clonal population of transfected NK-92 cells, comprising: transfecting NK-92 cells with a multi-cistronic nucleic acid vector comprising a positive selection marker and at least one transgene.
Copending claim 4 recites wherein the at least one transgene encodes an Fc Receptor.
Copending claim 5 recites that the Fc Receptor is CD 16.
The main difference between the present claims and the copending claims is that the present claims recite that the modified cells comprise genomic integration of a nucleic acid encoding CD16 and do not express IL-2. However, CAMPBELL teaches these differences. The teachings of CAMPBELL, MA, and SHADPOUR, and how they relate to the claims, are set forth in the rejections under 35 U.S.C. 102 and 103 above.
Because the copending claims recite a clonal population of transfected NK-92 that express CD16, and CAMPBELL teaches that the modified cells comprise genomic integration of a nucleic acid encoding CD16 and do no express IL-2, it would have been obvious to one having ordinary skill in the art to use the copending claims’ clonal population of transfected NK-92 cells the present claims.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1, 3 – 6, 8, 11 – 13, 18 – 27, and 29 – 33 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Estella Gustilo whose telephone number is (703)756-1706. The examiner can normally be reached Monday - Friday 9:30 AM - 5:30 PM.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/PETER J REDDIG/Primary Examiner, Art Unit 1646
APPENDIX
Alignment with SEQ ID NO: 1
BBV31364
ID BBV31364 standard; protein; 254 AA.
XX
AC BBV31364;
XX
DT 23-APR-2015 (first entry)
XX
DE Human Fc gamma RIII-A (CD16) protein mutant F176V.
XX
KW CD16; Fc gamma RIII-A; Immunoglobulin gamma Fc receptor III;
KW Immunoglobulin gamma Fc region receptor III-A; antibody therapy; antigen;
KW antimicrobial-gen.; cancer; cell death; cytostatic; infectious disease;
KW mutein; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Misc-difference 176
FT /note= "Wild-type Phe substituted by Val"
XX
CC PN AU2014280879-A1.
XX
CC PD 22-JAN-2015.
XX
CC PF 22-DEC-2014; 2014AU-00280879.
XX
PR 10-JAN-2013; 2013AU-00200124.
XX
CC PA (FOXC-) FOX CHASE CANCER CENT.
XX
CC PI Campbell KS;
XX
DR WPI; 2015-11051C/15.
XX
CC PT In vitro assessment of efficacy of antibody to induce cell death, by
CC PT exposing target cell to antibody binds to antigen expressed by target
CC PT cell, exposing target cell to natural killer-92 cell, and monitoring
CC PT cytolysis Of target cell.
XX
CC PS Example 8; Page; 98pp; English.
XX
CC The present invention relates to a novel method for in vitro assessment
CC of efficacy of an antibody to induce cell death. The method comprises (a)
CC exposing a target cell to the antibody that specifically binds to an
CC antigen expressed by the target cell, (b) exposing the target cell to a
CC modified natural killer (NK)-92 cell expressing an Fc receptor comprising
CC CD16 (Fc gamma RIII-A), and (c) monitoring the target cell for
CC cytotoxicity, cytolysis, or apoptosis. The invention further provides a
CC method for treating tumor, infection or other lesion in a subject, by
CC administering the antibodies that specifically bind to the tumor,
CC infection or other lesion to the subject, and (b) administering the
CC modified NK-92 cells expressing the Fc receptor comprising CD16 to the
CC subject. The present sequence represents a human low affinity
CC immunoglobulin gamma Fc region receptor III-A (Fc gamma RIII-A/CD16)
CC protein mutant F176V, which is used in the method for in vitro assessment
CC of efficacy of the antibody to induce cell death. Note: The present
CC sequence is not shown in the specification but is derived from the human
CC CD16 sequence given in table 1 (see BBV31353), based on the information
CC provided on page 60a, in example 8 of the specification.
XX
SQ Sequence 254 AA;
ALIGNMENT:
Query Match 100.0%; Score 1359; Length 254;
Best Local Similarity 100.0%;
Matches 254; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MWQLLLPTALLLLVSAGMRTEDLPKAVVFLEPQWYRVLEKDSVTLKCQGAYSPEDNSTQW 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MWQLLLPTALLLLVSAGMRTEDLPKAVVFLEPQWYRVLEKDSVTLKCQGAYSPEDNSTQW 60
Qy 61 FHNESLISSQASSYFIDAATVDDSGEYRCQTNLSTLSDPVQLEVHIGWLLLQAPRWVFKE 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FHNESLISSQASSYFIDAATVDDSGEYRCQTNLSTLSDPVQLEVHIGWLLLQAPRWVFKE 120
Qy 121 EDPIHLRCHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFCRGLVGSKN 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 EDPIHLRCHSWKNTALHKVTYLQNGKGRKYFHHNSDFYIPKATLKDSGSYFCRGLVGSKN 180
Qy 181 VSSETVNITITQGLAVSTISSFFPPGYQVSFCLVMVLLFAVDTGLYFSVKTNIRSSTRDW 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VSSETVNITITQGLAVSTISSFFPPGYQVSFCLVMVLLFAVDTGLYFSVKTNIRSSTRDW 240
Qy 241 KDHKFKWRKDPQDK 254
||||||||||||||
Db 241 KDHKFKWRKDPQDK 254
Alignment with SEQ ID NO: 2
BBV31364
ID BBV31364 standard; protein; 254 AA.
XX
AC BBV31364;
XX
DT 23-APR-2015 (first entry)
XX
DE Human Fc gamma RIII-A (CD16) protein mutant F176V.
XX
KW CD16; Fc gamma RIII-A; Immunoglobulin gamma Fc receptor III;
KW Immunoglobulin gamma Fc region receptor III-A; antibody therapy; antigen;
KW antimicrobial-gen.; cancer; cell death; cytostatic; infectious disease;
KW mutein; therapeutic.
XX
OS Homo sapiens.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Misc-difference 176
FT /note= "Wild-type Phe substituted by Val"
XX
CC PN AU2014280879-A1.
XX
CC PD 22-JAN-2015.
XX
CC PF 22-DEC-2014; 2014AU-00280879.
XX
PR 10-JAN-2013; 2013AU-00200124.
XX
CC PA (FOXC-) FOX CHASE CANCER CENT.
XX
CC PI Campbell KS;
XX
DR WPI; 2015-11051C/15.
XX
CC PT In vitro assessment of efficacy of antibody to induce cell death, by
CC PT exposing target cell to antibody binds to antigen expressed by target
CC PT cell, exposing target cell to natural killer-92 cell, and monitoring
CC PT cytolysis Of target cell.
XX
CC PS Example 8; Page; 98pp; English.
XX
CC The present invention relates to a novel method for in vitro assessment
CC of efficacy of an antibody to induce cell death. The method comprises (a)
CC exposing a target cell to the antibody that specifically binds to an
CC antigen expressed by the target cell, (b) exposing the target cell to a
CC modified natural killer (NK)-92 cell expressing an Fc receptor comprising
CC CD16 (Fc gamma RIII-A), and (c) monitoring the target cell for
CC cytotoxicity, cytolysis, or apoptosis. The invention further provides a
CC method for treating tumor, infection or other lesion in a subject, by
CC administering the antibodies that specifically bind to the tumor,
CC infection or other lesion to the subject, and (b) administering the
CC modified NK-92 cells expressing the Fc receptor comprising CD16 to the
CC subject. The present sequence represents a human low affinity
CC immunoglobulin gamma Fc region receptor III-A (Fc gamma RIII-A/CD16)
CC protein mutant F176V, which is used in the method for in vitro assessment
CC of efficacy of the antibody to induce cell death. Note: The present
CC sequence is not shown in the specification but is derived from the human
CC CD16 sequence given in table 1 (see BBV31353), based on the information
CC provided on page 60a, in example 8 of the specification.
XX
SQ Sequence 254 AA;
ALIGNMENT:
Length: 254
Score: 1359.00 Matches: 254
Percent Similarity: 100.0% Conservative: 0
Best Local Similarity: 100.0% Mismatches: 0
Query Match: 94.2% Indels: 0
Gaps: 0
US-17-295-010-2 (1-765) x ABM80203 (1-254)
Qy 1 ATGTGGCAGCTGCTGCTGCCTACAGCTCTCCTGCTGCTGGTGTCCGCCGGCATGAGAACC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MetTrpGlnLeuLeuLeuProThrAlaLeuLeuLeuLeuValSerAlaGlyMetArgThr 20
Qy 61 GAGGATCTGCCTAAGGCCGTGGTGTTCCTGGAACCCCAGTGGTACAGAGTGCTGGAAAAG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 21 GluAspLeuProLysAlaValValPheLeuGluProGlnTrpTyrArgValLeuGluLys 40
Qy 121 GACAGCGTGACCCTGAAGTGCCAGGGCGCCTACAGCCCCGAGGACAATAGCACCCAGTGG 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 41 AspSerValThrLeuLysCysGlnGlyAlaTyrSerProGluAspAsnSerThrGlnTrp 60
Qy 181 TTCCACAACGAGAGCCTGATCAGCAGCCAGGCCAGCAGCTACTTCATCGACGCCGCCACC 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PheHisAsnGluSerLeuIleSerSerGlnAlaSerSerTyrPheIleAspAlaAlaThr 80
Qy 241 GTGGACGACAGCGGCGAGTATAGATGCCAGACCAACCTGAGCACCCTGAGCGACCCCGTG 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 81 ValAspAspSerGlyGluTyrArgCysGlnThrAsnLeuSerThrLeuSerAspProVal 100
Qy 301 CAGCTGGAAGTGCACATCGGATGGCTGCTGCTGCAGGCCCCCAGATGGGTGTTCAAAGAA 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 101 GlnLeuGluValHisIleGlyTrpLeuLeuLeuGlnAlaProArgTrpValPheLysGlu 120
Qy 361 GAGGACCCCATCCACCTGAGATGCCACTCTTGGAAGAACACCGCCCTGCACAAAGTGACC 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GluAspProIleHisLeuArgCysHisSerTrpLysAsnThrAlaLeuHisLysValThr 140
Qy 421 TACCTGCAGAACGGCAAGGGCAGAAAGTACTTCCACCACAACAGCGACTTCTACATCCCC 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 141 TyrLeuGlnAsnGlyLysGlyArgLysTyrPheHisHisAsnSerAspPheTyrIlePro 160
Qy 481 AAGGCCACCCTGAAGGACTCCGGCTCCTACTTCTGCAGAGGCCTCGTGGGCAGCAAGAAC 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 161 LysAlaThrLeuLysAspSerGlySerTyrPheCysArgGlyLeuValGlySerLysAsn 180
Qy 541 GTGTCCAGCGAGACAGTGAACATCACCATCACCCAGGGCCTGGCCGTGTCTACCATCAGC 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 ValSerSerGluThrValAsnIleThrIleThrGlnGlyLeuAlaValSerThrIleSer 200
Qy 601 AGCTTTTTCCCACCCGGCTACCAGGTGTCCTTCTGCCTCGTGATGGTGCTGCTGTTCGCC 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 201 SerPhePheProProGlyTyrGlnValSerPheCysLeuValMetValLeuLeuPheAla 220
Qy 661 GTGGACACCGGCCTGTACTTCAGCGTGAAAACAAACATCAGAAGCAGCACCCGGGACTGG 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 221 ValAspThrGlyLeuTyrPheSerValLysThrAsnIleArgSerSerThrArgAspTrp 240
Qy 721 AAGGACCACAAGTTCAAGTGGCGGAAGGACCCCCAGGACAAG 762
||||||||||||||||||||||||||||||||||||||||||
Db 241 LysAspHisLysPheLysTrpArgLysAspProGlnAspLys 254
Prosecution Insights