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 remarks and amendments filed 6-10-26 are acknowledged.
Claims 79-94 are pending and under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The prior rejections of record have been withdrawn in view of applicant’s claim amendments.
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.
Claims 79-87 and 89-94 are rejected under 35 U.S.C. 103 as being unpatentable over Ullman et al. (WO2017062888A1, cited on an IDS) in view of Nagorsen et al. (Pharmacology & Therapeutics 136 (2012) 334–342, cited on an IDS), Jutz et al. (Journal of Immunological Methods 430 (2016) 10–20, cited on an IDS) and Frankel et al. (Current Opinion in Chemical Biology 2013, 17:385–392, cited on an IDS) as evidenced by, Dong et al. (INFECTION AND IMMUNITY, Jan. 1999, p. 220–229, cited on an IDS).
Ullman teaches a “bispecific mode” bioassay wherein “a bispecific antibody composed of one Fab arm that binds to CD3 on T cells and a second Fab binding to CD20 on HEK293 cells (CD3xCD20 bispecific antibody; e.g., as disclosed in US20140088295) was utilized. The presence of the bispecific molecule results in the formation of an immunological synapse and activation of the TCR complex due to clustering of the CD3 molecules on the engineered T-cells.” (see Example 8, in particular paragraph 269 and Fig. 1A).
The “engineered T-cells” of Example 8 and Fig. 1A are a Jurkat derived T cell clone, “JRT3.T3.5” (which is a CD4+ T cell line), comprising a firefly luciferase reporter gene driven by an AP-1 promoter (see paragraphs 266 and 276).
The assay of Ullman was designed to monitor the effect of anti-LAG3 antibody on interaction of T-cell expressed LAG-3 and APC expressed MHC class II, said LAG3/MHCII interaction inhibiting T-cell activation by shutting down positive signals initiated by the TCR signalosome (see paragraphs 264 and 268).
However, Ullman does not explicitly teach “[a] method for determining the specificity of a T cell dependent bispecific antibody (TDB)…,” comprising steps a), b) and c) as recited in claim 79 and dependent claims thereof.
The ordinarily skilled artisan was well aware that T cell dependent bispecific (TDB) antibodies, such as the CD19xCD3 TDB known as “blinatumomab,” exhibit exceptional potency in vivo, even at very low serum levels such as 0.6-1 ng/mL (see, e.g., Nagorsen at page 335, right col., 1st full paragraph and at page 339, right col., last paragraph).
The ordinarily skilled artisan was further well aware that in some instances tumor associated antigens can be expressed by non-tumor cells, and in such a scenario on-target but off-tumor recognition was likewise well known to cause toxicity (see, e.g., Frankel at page 388, right col., 1st full paragraph).
Given this knowledge in the art, it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to use the bioassay of Ullman in “bispecific mode” to detect if a given TDB will activate T-cells (as reflected by firefly luciferase reporter activity), e.g., even when the TDB target antigen was expressed by target cells at a low concentration, and further to perform a control assay comprising the TDB, T-cells and target cells lacking expression of the target antigen.
It was a well-known, common practice in the cell and molecular biology arts to include various controls for any bioassay, including inter alia, a “negative control,” so as to ensure that the signal observed in the test assessment is dependent of the presence of that which was missing from the negative control, as opposed to any of the test sample signal coming from an unexpected / not anticipated stimulus.
Given this knowledge in the art, it would have been obvious to one of ordinary skill in the art to determine the specificity of a T cell dependent bispecific antibody (TDB) via a method wherein first the ability of the TDB to activate T-cells in the presence of target cell expressing the TDB recognized antigen is measured, e.g., measuring expression of a T cell activation reporter such as a firefly luciferase reporter gene driven by an AP-1 promoter, second the ability of the TDB to activate T-cells in the presence of target cell that does not express the TDB recognized antigen is measured using the same reporter system (the negative control), and finally the level of firefly luciferase reporter gene expression measured in the first step was compared to the level of firefly luciferase reporter gene expression measured in the second step to assess the ability of the TDB to be specifically activated by the appropriate target cells (expressing the TDB recognized antigen), and further to not be activated by cells that do not express the TDB recognized antigen (the negative control).
It would be obvious to one of ordinary skill in the art that practicing such a technique would allow the ordinarily skilled artisan to measure the potency of any given TDB to trigger T-cell activation, even in those instances where the TDB target antigen is expressed at very low levels in a given target cell. With regard to the latter in particular, note that such a negative control would be obviously recognized to be of added importance in the context of an experimental system where lower levels of positive stimulus were expected to induce a lower levels of reporter gene expression which could, in turn, be more readily mimicked by a negative control, i.e., by a control lacking the positive stimulus. One reason the ordinarily skilled artisan would have been motivated to use the bioassay of Ullman in bispecific mode was because such a bioassay was based on a Jurkat-derived T cell clone and was thus thought to be less complex and time consuming than bioassays based on, e.g., primary T cells (see Jutz at page 18, right col., lines 6-9).
The bispecific mode assay described in Example 8 of Ullman was performed at ratio of 5 reporter T-cells : 1 APC / target cell (see paragraphs 269-71 of Ullman wherein “APC” = a HEK 293 cell line expressing human CD20 as described in paragraph 267). Moreover, in Example 8 of Ullman a particular bispecific anti-CD3xanti-CD20 antibody was used, the bispecific antibody disclosed in US20140088295, at a concentration of 100 pM. Thus, it would be obvious to the ordinarily skilled artisan that the bispecific mode assay described in Example 8 of Ullman was designed to ensure maximum CD3 signalling so as to best assess the ability of the anti-LAG3 antibody to shut down the TCR signalosome.
However, when conducting an assay to assess the potency of a given TDB to trigger T-cell activation, even when the triggering target antigen was present at very low level (by contrast to the bispecific mode assay described in Example 8 of Ullman), it would have been obvious to one of ordinary skill in the art to make use of excess of target antigen expressing cells relative to reporter T-cells so as to best ensure that the presence of the TDB antigen, even when expressed at low levels, will trigger reporter gene expression, and that this observed reporter gene expression will exceed whatever reporter gene expression occurs in the negative control. Thus, it would have been obvious to one of ordinary skill in the art to perform a method for detecting very low concentration TDB with an excess of target cells to T cells as recited in claims 89 and 90.
Moreover, note that insofar as the reference teachings do not recite the particular ratios of t-cells to test cells / t-cells to target cells recited in claims 89-90, Applicant’s attention is further drawn to MPEP 2144.05(II)(A), Routine Optimization - Optimization Within Prior Art Conditions or Through Routine Experimentation:
“Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).”
Although this passage does not specifically point to, for example, the particular ratios of t-cells to test cells / t-cells to target cells recited in claims 89-90, this passage points to numerous variables that generally affect the function of inventions, including concentration of reagents. Furthermore this passage indicates that the optimization of such variables is often an obvious activity for one of ordinary skill in the art. It is submitted that the particular ratios of t-cells to test cells / t-cells to target cells recited in claims 89-90 are akin to the variables discussed in the cited MPEP passage because said ratios of t-cells to test cells / t-cells to target cells are optimizable variables that would be expected to affect the sensitivity of the assay when, e.g., the target cell antigen recognized by the TDB is present at low concentrations.
Accordingly, the particular ratios of t-cells to test cells / t-cells to target cells recited in claims 89-90 represented a result-effective variable that was routinely manipulated to achieve a desired result; likewise, it is submitted that since one of ordinary skill in the art would have been motivated to determine the optimum or workable ranges of variables in a given bioassay, the particular ratios of t-cells to test cells / t-cells to target cells recited in claims 89-90 were prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention.
Along these same lines, as described above the ordinarily skilled artisan was well aware that T cell dependent bispecific (TDB) antibodies exhibit exceptional potency in vivo, even at very low serum levels such as 0.6-1 ng/mL, and thus in practicing a method for determining the specificity of a TDB it would be obvious to the ordinarily skilled artisan that the composition should be designed to assess TDB specificity even at very low levels, e.g., at 0.6-1 ng/mL, which falls within the range set forth in claim 93.
With respect to the obviousness of practicing the method of claim 79 with certain amounts of total cells (claims 91-92), the bispecific mode assay described in Example 8 of Ullman is performed with a total of 6x104 APC target cells + reporter T-cells. Thus, the ordinarily skilled artisan would have been motivated to perform an assay for determining the specificity of a T cell dependent bispecific antibody (TDB) using a similar amount of total cells.
With respect to the obviousness of practicing the method of claim 94 wherein the expression of the reporter is detected after a certain number of hours, as described by Ullman, the reporter T-cells and APC target cells are incubated for 4-6 hours before detecting firefly luciferase activity (see paragraph 271). Thus, the ordinarily skilled artisan would have been motivated to perform an assay for detecting a T cell dependent bispecific antibody (TDB) in a composition using a similar incubation timeframe.
With respect to the particular population of T-cells used in the reporter assay (claim 84), it would have been obvious to the ordinarily skilled artisan to use the same T-cell population as was used by Ullman, i.e., the Jurkat derived T cell clone, JRT3.T3.5 (ATCC, # TIB- 153), which is a CD4+ T-cell clone as evidenced by Dong at “Cell lines” on page 221, left col.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 83-87, 89, 90, 93 and 94 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al. Promega Poster: "Development of a Robust Reporter-based T cell Activation Assay for Therapeutic Biologics in Immunotherapy,” May 2, 2014, 1 page (cited herewith), in view of Nagorsen et al. (Pharmacology & Therapeutics 136 (2012) 334–342) and Frankel et al. (Current Opinion in Chemical Biology 2013, 17:385–392, cited on an IDS), as evidenced by, Dong et al. (INFECTION AND IMMUNITY, Jan. 1999, p. 220–229)(cited on an IDS unless otherwise noted).
As a preliminary matter, the filing date for the Promega poster of Cheng et al. comes from the International Search Report for International Application No. PCT/EP2017/082112 (cited on an IDS) which states that the Cheng et al. poster was published 2 May 2014.
Cheng teaches a robust reporter-based assay that measures the ability of a CD3xTumor antigen binding bispecific antibody to activate Jurkat T-cells that have been stably modified with a “luciferase reporter” comprising a promoter sequence that is activated by NFAT binding (NFAT-RE), and, upon CD3 activation said promoter induces expression of the downstream luciferase gene (see Sections 1 and 2). Cheng teaches their bioassay has number of useful features (Section 3) and shows dose-dependent production of luciferase when the EpCAM+ target cell lines SK-BR-3 or MDA-MB-231 were incubated with the bispecific CD3xEpCAM therapeutic antibody known as catumaxomab (also known by the trade name “Removab”), see Section 5. Cheng shows in Section 7 that their assay has “Specificity” by virtue of its ability to distinguish between target cells that express the cognate antigen (EpCAM+ target cells SK-BR-3 and MDA-MB-231) as compared to target cells that are EpCAM- (Raji cells), or as compared to no target cells present (“without APC”). Cheng concludes, “The assay is specific, can be used for relative potency determination and shows good assay linearity.”
However, Cheng does not explicitly teach “[a] method for determining the specificity of a T cell dependent bispecific antibody (TDB)…,” comprising steps a), b) and c) as recited in claim 79 and dependent claims thereof.
The ordinarily skilled artisan was well aware that T-cell dependent, bispecific antibodies (TDB), such as the CD19xCD3 TDB known as “blinatumomab,” exhibit exceptional potency in vivo, even at very low serum levels such as 0.6-1 ng/mL (see, e.g., Nagorsen at page 335, right col., 1st full paragraph and at page 339, right col., last paragraph).
The ordinarily skilled artisan was further well aware that in some instances tumor associated antigens can be expressed by non-tumor cells, and in such a scenario on-target but off-tumor recognition was likewise well known to cause toxicity (see, e.g., Frankel at page 388, right col., 1st full paragraph).
Given this knowledge in the art, it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to use the bioassay of Cheng to detect if a given TDB will activate T-cells (as reflected by firefly luciferase reporter activity), e.g., even when the TDB target antigen was expressed by target cells at a low concentration, and further to perform a control assay comprising the TDB, T-cells and target cells lacking expression of the target antigen.
It was a well-known, common practice in the cell and molecular biology arts to include various controls for any bioassay, including inter alia, a “negative control,” so as to ensure that the signal observed in the test assessment is dependent of the presence of that which was missing from the negative control, as opposed to any of the test sample signal coming from an unexpected / not anticipated stimulus.
Indeed, Section 8 of Cheng includes a version of a “negative control” wherein the substantial production of luciferase in the presence of the EpCAM+ target cell lines SK-BR-3 or MDA-MB-231 is compared to the minimal production of luciferase in the presence of EpCAM- Raji target cells.
Given this knowledge in the art, it would have been obvious to one of ordinary skill in the art to determine the specificity of a T cell dependent bispecific antibody (TDB) via a method wherein first the ability of the TDB to activate T-cells in the presence of target cell expressing the TDB recognized antigen is measured, e.g., measuring expression of a T cell activation reporter such as a “luciferase reporter” comprising a promoter sequence that is activated by NFAT binding (NFAT-RE), and, upon CD3 activation said promoter induces expression of the downstream luciferase gene, second the ability of the TDB to activate T-cells in the presence of target cell that does not express the TDB recognized antigen is measured using the same reporter system (the negative control), and finally the level of luciferase reporter gene expression measured in the first step was compared to the level of luciferase reporter gene expression measured in the second step to assess the ability of the TDB to be specifically activated by the appropriate target cells (expressing the TDB recognized antigen), and further to not be activated by cells that do not express the TDB recognized antigen (the negative control).
It would be obvious to one of ordinary skill in the art that practicing such a technique would allow the ordinarily skilled artisan to measure the potency of any given TDB to trigger T-cell activation, even in those instances where the TDB target antigen is expressed at very low levels in a given target cell. With regard to the latter in particular, note that such a negative control would be obviously recognized to be of added importance in the context of an experimental system where lower levels of positive stimulus were expected to induce a lower levels of reporter gene expression which could, in turn, be more readily mimicked by a negative control, i.e., by a control lacking the positive stimulus. One reason the ordinarily skilled artisan would have been motivated to use the bioassay of Cheng for such a purpose was such a bioassay was based on a Jurkat-derived T cell clone and is thus simple in that it does not rely on primary effector cells and can be performed quickly as described in Section 3 of Cheng.
It further would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to use the bioassay of Cheng to determine if a given TDB binds its target antigen with “specificity” meaning that said TDB will substantially activate T-cells in the presence of test cells expressing the target antigen of said TDB while not being substantially activated by target cells which do not express the TDB target antigen (negative cells of the control). The ordinarily skilled artisan was motivated to determine if a given TDB had good specificity for cells expressing its target antigen given that TDB which is activated by non-target antigen has the potential to activate T-cell mediated toxicity.
While Cheng does not teach the particular amounts of target cells or reporter T-cells used in their bioassay, in conducting an assay to measure TDB specificity it would have been obvious to one of ordinary skill in the art that an excess of target antigen expressing cells relative to reporter T-cells will best ensure that even low-level binding to off-target antigens / low-level T-cell activation can be detected. Thus, it would have been obvious to one of ordinary skill in the art to perform a method for determining TDB specificity with an excess of target cells to T cells as recited in claims 89-90. Along these same lines, as described above the ordinarily skilled artisan was well aware that T cell dependent bispecific (TDB) antibodies exhibit exceptional potency in vivo, even at very low serum levels such as 0.6-1 ng/mL, and thus in practicing a method for determining TDB specificity it would be obvious to the ordinarily skilled artisan that the composition should be designed to detect the TDB at levels of around 0.6-1 ng/mL, which is encompassed by the range recited in claim 93.
With respect to the obviousness of practicing the method of claim 79 wherein the expression of the reporter is detected after a certain number of hours (claim 94), as described by Cheng their bioassay is conduced for 5 hours (see Section 3) and thus it would have been obvious to the ordinarily skilled artisan to incubate the reporter T-cells and target cells for 5 hours before detecting luciferase activity.
With respect to the particular population of T-cells used in the reporter assay (claim 84), it would have been obvious to the ordinarily skilled artisan to use the same T-cell population as was used by Cheng, i.e., Jurkat reporter cells which are CD4+ as evidenced by Dong at “Cell lines” on page 221, left col.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim 88 is rejected as being unpatentable over the teachings of Ullman et al. (WO2017062888A1, of record) in view of Nagorsen et al. (Pharmacology & Therapeutics 136 (2012) 334–342), Jutz et al. (Journal of Immunological Methods 430 (2016) 10–20) and Frankel et al. (Current Opinion in Chemical Biology 2013, 17:385–392) as evidenced by Dong et al. (INFECTION AND IMMUNITY, Jan. 1999, p. 220–229) as applied to claims 79-87 and 89-94 above, OR
over the teachings of Cheng et al. Promega Poster: "Development of a Robust Reporter-based T cell Activation Assay for Therapeutic Biologics in Immunotherapy,” May 2, 2014, 1 page (cited herewith), in view of Nagorsen et al. (Pharmacology & Therapeutics 136 (2012) 334–342) and Frankel et al. (Current Opinion in Chemical Biology 2013, 17:385–392, cited on an IDS), as evidenced by, Dong et al. (INFECTION AND IMMUNITY, Jan. 1999, p. 220–229) as applied to claims 83-87, 89, 90, 93 and 94 above,
each further in view of Junttila et al. (Cancer Res; 74(19); pages 5561–71 and Supplementary pages 1-9 (2014))(cited on an IDS).
Juntilla describes a T-cell dependent bispecific antibody (TDB) that redirects the cytotoxicity of T-cells through CD3 binding to Her-2 expressing cancer cells (see Abstract and Introduction). Juntilla characterizes the cytotoxicity of this antibody using assays wherein the Her2-expressing target cells are SKBR3 cells (see, e.g., at page 5563, right col., 1st section and Supplemental Fig. S1A). Given that Her2-expressing SKBR3 cells induce potent HER2-TDB killing via T-cell activation it would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to use Her2-expressing SKBR3 cells as target cells in an assay to determine the specificity of Her2xCD3 bispecific antibodies.
In view of the reference teachings it was apparent that one of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
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 79-94 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11513127 in view of Cheng et al. Promega Poster: "Development of a Robust Reporter-based T cell Activation Assay for Therapeutic Biologics in Immunotherapy,” May 2, 2014, 1 page (cited herewith).
Reference claims 1-12 are as follows:
1. A method for detecting a T cell dependent bispecific antibody (TDB) in a composition, wherein the TDB comprises a target antigen binding fragment and a CD3 binding fragment, the method comprising contacting a population of T cells and target cells with the composition, wherein the T cells comprise nucleic acid encoding a reporter operably linked to a response element that is responsive to T cell activation, wherein the response element that is responsive to T cell activation is an NFκB promoter, and wherein the target cells express the target antigen; wherein expression of the reporter indicates the presence of the TDB.
2. The method of claim 1, wherein the reporter is a luciferase, a fluorescent protein, an alkaline phosphatase, a beta lactamase, or a beta galactosidase.
3. The method of claim 2, wherein the luciferase is a firefly luciferase, a Renilla luciferase, or a nanoluciferase.
4. The method of claim 1, wherein the population of T cells is a population of CD4.sup.+T cells or CD8.sup.+T cells.
5. The method of claim 1, wherein the population of T cells is a population of Jurkat T cells or CTLL-2 T cells.
6. The method of claim 1, wherein the target antigen is expressed on the surface of the target cell.
7. The method of claim 1, wherein the target antigen is CD4, CD8, CD18, CD19, CD11a, CD11b, CD20, CD22, CD34, CD40, CD79α (CD79a), CD79β (CD79b), EGF receptor, HER2 receptor, HER3 receptor, HER4 receptor, FcRH5, CLL1, LFA-1, Mac1, p150, 95, VLA-4, ICAM-1, VCAM, αv/β3 integrin, VEGF, flk2/flt3 receptor; obesity (OB) receptor; mpl receptor; CTLA-4; protein C, BR3, c-met, tissue factor, β7, Tenb2, STEAP, or transmembrane tumor-associated antigens (TAA).
8. The method of claim 1, wherein a) the target antigen is HER2 receptor and the target cell is a BT-474 cell, b) the target antigen is HER2 receptor and the target cell is a SKBR3 cell, c) the target antigen is CD20 and the target cell is a Wil2-S cell, or d) the target antigen is CD79b and the target cell is a BJAB cell.
9. The method of claim 1, wherein the ratio of T cells to target cells in the population of cells is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9 or about 1:10.
10. The method of claim 1, wherein the population of cells ranges from about 1×10.sup.3 to about 1×10.sup.6 cells or about 1×10.sup.4 to about 5×10.sup.4 cells.
11. The method of claim 1, wherein the population of T cells is contacted with a composition comprising the TDB at a concentration ranging from 0.01 ng/mL to 50 ng/mL.
12. The method of claim 1, wherein the reporter is detected after 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, or 24 hours after contacting the cells with the composition.
However, the reference claims are not drawn to methods of determining TDB specificity.
Cheng teaches a robust reporter-based assay that measures the ability of a CD3xTumor antigen binding bispecific antibody to activate Jurkat T-cells that have been stably modified with a “luciferase reporter” comprising a promoter sequence that is activated by NFAT binding (NFAT-RE), and, upon CD3 activation said promoter induces expression of the downstream luciferase gene (see Sections 1 and 2). Cheng teaches their bioassay has number of useful features (Section 3) and shows dose-dependent production of luciferase when the EpCAM+ target cell lines SK-BR-3 or MDA-MB-231 were incubated with the bispecific CD3xEpCAM therapeutic antibody known as catumaxomab (also known by the trade name “Removab”), see Section 5. Cheng shows in Section 7 that their assay has “Specificity” by virtue of its ability to distinguish between target cells that express the cognate antigen (EpCAM+ target cells SK-BR-3 and MDA-MB-231) as compared to target cells that are EpCAM- (Raji cells), or as compared to no target cells present (“without APC”). Cheng concludes, “The assay is specific, can be used for relative potency determination and shows good assay linearity.”
Given the reference claims and the teachings of Cheng set forth above, it would have been obvious to one of ordinary skill in the art to modify the “method for detecting a T cell dependent bispecific antibody (TDB) in a composition, wherein the TDB comprises a target antigen binding fragment and a CD3 binding fragment” of the reference claims to instead practice a method of determining the specificity of a TDB by first measuring the ability of the TDB to activate T-cells in the presence of test cells that do not express the TDB recognized antigen (again as reflected by expression of a nucleic acid encoding a reporter operably linked to a response element that is responsive to T cell activation), by second measuring the ability of the TDB to activate T-cells in the presence of target cell expressing the TDB recognized antigen (as reflected by expression of a nucleic acid encoding a reporter operably linked to a response element that is responsive to T cell activation), and finally comparing expression of the reporter gene in the first measurement to the expression of the reporter gene in the second measurement wherein the smaller the ratio the greater the specificity of the TDB.
It would be obvious to one of ordinary skill in the art that practicing such a technique would allow the ordinarily skilled artisan to measure the potency of any given TDB to trigger T-cell activation, even in those instances where the TDB target antigen is expressed at very low levels in a given target cell. With regard to the latter in particular, note that such a negative control would be obviously recognized to be of added importance in the context of an experimental system where lower levels of positive stimulus were expected to induce a lower levels of reporter gene expression which could, in turn, be more readily mimicked by a negative control, i.e., by a control lacking the positive stimulus. One reason the ordinarily skilled artisan would have been motivated to use the bioassay of Cheng for such a purpose was such a bioassay was based on a Jurkat-derived T cell clone and is thus simple in that it does not rely on primary effector cells and can be performed quickly as described in Section 3 of Cheng.
It further would have been obvious to one of ordinary skill in the art, and one of ordinary skill in the art would have been motivated to use the bioassay of Cheng to determine if a given TDB binds its target antigen with “specificity” meaning that said TDB will substantially activate T-cells in the presence of test cells expressing the target antigen of said TDB while not being substantially activated by target cells which do not express the TDB target antigen (negative cells of the control). The ordinarily skilled artisan was motivated to determine if a given TDB had good specificity for cells expressing its target antigen given that TDB which is activated by non-target antigen has the potential to activate T-cell mediated toxicity.
No claims are allowed.
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).
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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