Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claims 1-13 are pending and under examination.
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 1-16 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.
In claim 1 (and dependent claims thereof) the phrase “wherein the living cells…maintain their identity and at least one of the functional characteristics of the cells that defined the living cells prior to formulation” is indefinite. The “identity” of a given cell and the functional characteristics that "define" a given cell are relative, subjective terms that mean different things to different skilled artisans. For example, some skilled artisan may consider the “identity” of a given cell or its “defining" characteristics as the total of all its expressed genes while another skilled artisan may focus only on the expression of cell surface molecules like CD3 and CD4. The metes and bounds of the claimed invention cannot be established in the midst of such ambiguity.
In claims 9, 15 and 16, the phrase "cells...are stable for at least about 24/48/72 hours" the word “stable” is a relative, subjective term that means different things to different skilled artisans. Being stable for viability? Being stable for levels of expression of some functional characteristic but not necessarily others? Being stable for not dividing?
Claim 1 recites the cells are “stored for greater than about 6 hours." The meaning of "stored for greater than about 6 hours” is not defined by the claims and the specification does not provide a standard for ascertaining the requisite degree. “Stored for greater than about 6 hours” is a relative phrase and different artisans may have different opinions as to how many hours less than or greater than 6 hours will qualify as “stored for greater than about 6 hours.” Second, if "stored for greater than about 6 hours” is considered to be some non-defined range of hours greater than and less than 6 then if the living cells were to be stored, for example, for 4 hours in the non-nutritive buffer, and shown to meet the functional features of the instant claims after such storage, or for 7 hours in the non-nutritive buffer, and shown to meet the functional features of the instant claims after such storage, but these same cells did not meet the functional features of the instant claims when stored for 8 hours, then would such cells be encompassed by the instant claims or not? Would such cells be said to be encompassed by the claimed invention after storage for 4 or 7 hours, but not after storage for 8 hours, or should the claims be interpreted in some other manner? Different skilled artisan would have different, often conflicting opinions as to how the scope of the instant claims should be interpreted.
In conclusion, the metes and bounds of these aspects of claim 1 and dependent claims thereof are not clear and definite for the reasons set forth above.
The following is a quotation of the appropriate paragraphs of pre-AIA 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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claim(s) 1 and 3-16 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Hollyman et al. (J Immunother 2009;32:169–180) as evidenced by Brentjens et al. (Clin Cancer Res 2007;13:5426-5435)(all cited on an IDS).
As a preliminary matter, note that in one embodiment the instant claims given their broadest reasonable interpretation consistent with the teachings of the instant specification encompass in their breadth a biological drug composition comprising “living cells,” meaning that >70% of the cells are viable “as determined by appropriate assay techniques” (see, e.g., at paragraph 43), and further that said cells may have been isolated from peripheral blood cells, e.g., said cells may comprise Th1-type T-cells, and that said cells may have been frozen, i.e., cryopreserved, thawed and expanded by incubating with Dynabeads CD3/CD28, and then formulated in a non-nutritive buffer, e.g., plasmalyte + 1% HSA, wherein the living cells, after being stored for greater than about 6 hours in the non-nutritive buffer, maintain their identity and at least one functional characteristic that defined the living cells prior to formulation in the non-nutritive buffer, and finally that the living cells remain useful in immunotherapy after storage in the non-nutritive buffer (see, e.g., at paragraph 12).
Hollyman teaches the production of a biological drug composition comprising predominately CD4+ T cells (see Table 2, right-most col.) which is useful for immunotherapy comprising formulating the composition comprising living CD4+ T cells in plasmalyte + 1% HSA and maintaining the cells in said buffer at a temperature of 4°C for at least about 72 hours (see page 170-171 bridging paragraph; page 175, left col. 2nd paragraph; page 177, col. bridging paragraph).
More particularly, as taught by Hollyman peripheral blood cells are isolated and frozen, i.e., cryopreserved, thawed, then expanded by incubation with Dynabeads covalently linked, i.e., “cross-linked by…immobilization on a solid surface” (see spec at [0048]), to anti-CD3/anti-CD28 antibodies, followed by formulation in a non-nutritive buffer (plasmalyte + 1 % HSA), and maintained at a temperature of 4°C for up to four days with viability greater than 80% at 48 hours and from 74-79% at 72 hours, the cells formulated in said non-nutritive buffer maintaining a cell marker indicative of living cells and maintaining at least one functional characteristic exhibited by living cells and remaining useful for immunotherapy after being stored for greater than about 24 hours in the non-nutritive buffer (see page 170, right col., 1st full paragraph - page bridging paragraph; page 175, right col., 1st paragraph; page 177 col. bridging paragraph; Figure 1 and Table 4).
With regard to the “Stability of the Formulated 1928z+ T Cells” which will be infused into patients in a clinical trial, Hollyman specifically teaches:
“Formulated EOP cells from VR1 and VR2 were placed at 4°C and the viability was tested at 24, 48, 72, and 96 hours. EOP cells from both VR1 and VR2 were greater than 80% viable after 48 hours at 4ºC (data not shown). The viability at 72 hours was 74% and 79% and 70% and 78% at 96 hours in VR1 and VR2, respectively. Our specification for T-cell infusion requires a minimum of 80% viability. We have therefore set our expiration date for 1928z-transduced T cells at 48 hours after final formulation.”
(see page 177 col. bridging paragraph, emphasis added).
Hollyman also teaches cell densities of their final immobilized anti-CD3 / anti-CD28 antibody (dynabeads) expanded composition of CD4+ T cells ranged from 13-31 x 106 cells/mL (see Fig. 2B, Table 2 and associated text). At page 178-179 bridging paragraph, Hollyman teaches the CD4 content of the final formulation of cells ranged from 12:1 to 1.7:1, CD4:CD8 (see also Table 2). Finally, at page 179, left col., 2nd full paragraph, Hollyman teaches “The immunophenotype of the expanded 1928z+ EOP T cells at the end of the runs correlates best with that of effector T cells still expressing significant levels of CD28 and CD27. Importantly, these effector T cells were derived not only from T cells with an effector phenotype but also from T cells in the apheresis product that display a memory phenotype.37-39”
Thus, the teachings of Hollyman set forth above anticipate the compositions of claims 1, 3, 9-11, 13, 15 and 16.
As to claims reciting that the living cells maintain certain levels of CD40L expression (see claims 7 and 14), or certain levels of IFNγ secretion after storage (see claim 8), or that the “the living cells are activated Th1 cells” (see claims 4-6 and 12), given
the cells of Hollyman are substantially similar to the cells of the instant specification in that they are predominately CD4+ T cells having been activated by anti-CD4/CD28 dynabead and formulated in plasmalyte + 1% HSA, and
Brentjens (ref. # 12 of Hollyman) teaches the 1928z T-cells of Hollyman secrete the Th1 type cytokines IFN-γ and IL-2 when stimulated with their cognate antigen (see Brentjens at Fig. 2 and page 5430 bridging paragraph),
one of ordinary skill in the art practicing the teachings of Hollyman would necessarily be making the biologic drug compositions of claims 4-8 and 12 in addition to claims 1, 3, 9-11, 13, 15 and 16 for the reasons given above.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 2 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Hollyman et al. (J Immunother 2009;32:169–180) as evidenced by Brentjens et al. (Clin Cancer Res 2007;13:5426-5435) as applied to claims 1 and 3-16 above, and further in view of Jones et al. (COLD-CHAIN LOGISTICS: A STUDY OF THE DEPARTMENT OF THE DEFENSE OCONUS PRE-PANDEMIC VACCINE DISTRIBUTION NETWORK, Naval Postgraduate School, December 2007, pages i-xvi and 1-57)(all cited on an IDS).
The teachings of Hollyman as evidenced by Brentjens as applied to claims 1 and 3-16 are set forth above.
Moreover, at page 173 col. bridging paragraph Hollyman further teaches during the large-scale bioprocessing of 1928z+-transduced T Cells, “suitable levels of transduction could be achieved in tissue culture bags.”
However, Hollyman does not explicitly teach a biologic drug composition comprising living cells formulated in non-nutritive buffer, wherein the living cells, after being stored for greater than about 6 hours in the non-nutritive buffer, maintain their identity and at least one functional characteristic that defined the living cells prior to formulation in the non-nutritive buffer, the living cells useful in immunotherapy after storage in the non-nutritive buffer, “…wherein the living cells are placed in a flexible container or syringe, wherein the flexible container or syringe is packaged in a temperature controlled device,” as recited claim 2.
Jones teaches at page 15, last paragraph: “[t]he Endurotherm system is the insulated shipping container (ISC) and polar pack refrigerant of choice for the DLA. The combination of container, insulation, and refrigerant seen below is validated to maintain the required 2°C - 8°C (36°F - 46°F) temperature for 72 hours, exceeding current shipping contract times….” A picture of the endurotherm package and gel packs is shown on page 16 of Jones.
Given the reference teachings it would have been obvious to the ordinarily skilled artisan that:
(i) a need existed in the art to store/ship T cells for immunotherapy in an insulated shipping box that can maintain the cells at a cool temperature around about 0 to about 10 °C;
(ii) Jones taught such a cold-chain packaging container validated to maintain temperature in this range for 3 days; and thus
(iii) it would have been obvious to the ordinarily skilled artisan to modify the teachings of Hollyman to formulate the biological drug composition comprising 1928z+ CD4+ T cells in an infusion medium at a storage temperature between about 0 and about 10 °C for shipping in, e.g., a flexible container such as the “transduction” bag described by Hollyman, especially since,
the manufacturing process shown in Hollyman Fig. 1 was taught to require a semiclosed system and numerous specialized cell processing equipment the ordinarily skilled clinician at a point of care facility would not have had access to prior to applicant’s date of invention; and
Hollyman showed their formulated cells maintain greater than 80% viability after 48 hours at 4ºC, and “at least about 80%” after 72 hours, either of which would have been sufficient time periods to transport their 1928z+ transduced cells from their specialized manufacturing site to a point of care facility.
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 1-16 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Har-Noy (20040228848) in view of Hollyman et al. (J Immunother 2009;32:169–180), Brentjens et al. (Clin Cancer Res 2007;13:5426-5435), Kalamasz et al. (Blood, November 16, 2000, Vol. 96, No. 11 Part 2, pp. 316b) and Jones et al. (COLD-CHAIN LOGISTICS: A STUDY OF THE DEPARTMENT OF THE DEFENSE OCONUS PRE-PANDEMIC VACCINE DISTRIBUTION NETWORK, Naval Postgraduate School, December 2007, pages i-xvi and 1-57)(all cited on an IDS).
As a preliminary matter, note that in one embodiment the instant claims given their broadest reasonable interpretation consistent with the teachings of the instant specification encompass in their breadth a biological drug composition comprising “living cells,” meaning that >70% of the cells are viable “as determined by appropriate assay techniques” (see, e.g., at paragraph 43), and further that said cells may have been isolated from peripheral blood cells, e.g., said cells may comprise Th1-type T-cells, and that said cells may have been frozen, i.e., cryopreserved, thawed and expanded by incubating with Dynabeads CD3/CD28, and then formulated in a non-nutritive buffer, e.g., plasmalyte + 1% HSA, wherein the living cells, after being stored for greater than about 6 hours in the non-nutritive buffer, maintain their identity and at least one functional characteristic that defined the living cells prior to formulation in the non-nutritive buffer, and finally that the living cells remain useful in immunotherapy after storage in the non-nutritive buffer (see, e.g., at paragraph 12).
Har-Noy ‘848 teaches the production of a biological drug composition with living cells comprising isolating allogeneic CD4+ T-cells, activating said allogeneic CD4+ T-cells with monoclonal antibodies that are cross-linked such that the cells proliferate and differentiate into CD4+ Th1 cells, freezing said CD4+ Th1 cells, i.e., cryopreserving said CD4+ Th1 cells, thawing said CD4+ Th1 cells, formulating said CD4+ Th1 cells at a concentration of greater than 106 cells/mL in a non-nutritive buffer comprising plasmalyte supplemented with 0.5% - 10% HSA and packaged in a flexible container or syringe for infusion into a patient in need thereof (see, e.g., paragraphs 40-44; paragraphs 97-150, especially paragraphs 143-150; and claims 27, 33 and 52).
At paragraph 142 Har-Noy teaches “…To assure maximal cytokine production, the timing of the harvest should occur such that the cells are formulated and infused 24 hours after the last step 8-11 cycle.”
Har-Noy also teaches cells frozen in cryoprotective media supplemented with conditioned media from the expansion and differentiation of the CD4+ Th1 cells "maintain high cell viability.”
(see paragraph 0143).
Lastly, Har-Noy teaches it is preferred that the cells formulated in a non-nutritive buffer for infusion into a patient be formulated in the presence of activating mAbs that bind the T cell surface, such as mouse anti-human CD3 and mouse anti-human CD28, wherein biodegradable microspheres “are coated with an agent which reacts with the activating agents on the T-cells and causes them to be cross-linked and to deliver activation signals. Suitable coating agents for use with mouse mAbs include polyclonal anti-mouse antibodies or monoclonal anti-Fc mAbs.”
(see e.g. paragraphs 145 and 74-76).
However, Har-Noy ‘848 does not does explicitly teach “[a] biologic drug composition comprising living cells formulated in non-nutritive buffer, wherein the living cells, after being stored for greater than about 6 hours in the non-nutritive buffer, maintain their identity and at least one functional characteristic that defined the living cells prior to formulation in the non-nutritive buffer, the living cells useful in immunotherapy after storage in the non-nutritive buffer,” and dependent claims thereof.
Hollyman teaches the production of a biological drug composition comprising predominately CD4+ T cells (see Table 2, right-most col.) useful for immunotherapy comprising formulating the composition of CD4+ T cells in plasmalyte + 1% HSA and maintaining the cells in said formulation buffer at a temperature of 4°C for at least about 72 hours (see page 177, col. bridging paragraph). Hollyman further teaches cell densities of their final immobilized anti-CD3 / anti-CD28 antibody (dynabeads) expanded composition of CD4+ T cells ranged from 13-31 x 106 cells/mL (see Fig. 2B, Table 2 and associated text).
Brentjens (ref. # 12 of Hollyman) teaches the 1928z T-cells of Hollyman secrete the Th1 type cytokines IFN-γ and IL-2 when stimulated with their cognate antigen (see Fig. 2 and page 5430 bridging paragraph).
Kalamasz teaches a method for preparing living cells useful for immunotherapy comprising culturing T cells in the presence of paramagnetic microbeads coated with anti-CD3 and anti-CD28 antibodies (“Xcellerate T cells”).
According to Kalamasz “[f]reshly harvested Xcellerate T cells may be stored/shipped cold (4 to 8degreeC) or frozen in liquid nitrogen. The Xcellerate T cells (up to 30X109 cells) may be stored/shipped at 4 to 8degreeC by placing them in a medical grade plastic bag that contains an infusion grade isotonic solution supplemented with human serum albumin. The bag of cells (initially at room temperature) is placed in an insulated shipping box along with chilled Gel PacksTM. This method cools the cells and maintains them at 4-8degreeC for up to 48 hours. In testing this method with activated cells from healthy donors (n=4), after 48 hrs of storage/shipment, the T cells had a viability of 95 +- 3%. The cells stored for 48 hours also exhibited a strong response to restimulation (induced by exposure to Dynabeads(R) M-450 CD3/CD28 T), as indicated by an increase in their size (from 356 +- 74 to 574 +- 32 measured by forward light scatter units) and by an increase in their expression of the surface activation marker CD25 (from 35 +- 9 to 399 +-128 measured by mean fluorescence intensity)…. Clinical trials are now underway with Xcellerate cells stored/shipped at 4-8degreeC.”
Lastly, Jones teaches at page 15, last paragraph: “The Endurotherm system is the insulated shipping container (ISC) and polar pack refrigerant of choice for the DLA. The combination of container, insulation, and refrigerant seen below is validated to maintain the required 2°C - 8°C (36°F - 46°F) temperature for 72 hours, exceeding current shipping contract times (Dallas,1 personal communication, May 24, 2007).” A picture of the endurotherm package and gel packs is shown on page 16 of Jones.
Given the combined reference teachings it would have been obvious to the ordinarily skilled artisan that there exists a need in the art to store/ship T cells for immunotherapy in an insulated shipping box that can cool and maintain the cells at cool temperature around about 0 to about 10 °C. Moreover, given the teachings of Jones that cold-chain packaging like the endurotherm package and gel packs has been validated to maintain temperature in this cool range for 3 days, it further would have been obvious to one of ordinary skill in the art to modify the teachings of Har-Noy to formulate the biological drug composition comprising C4+, Th1 type T cells in an infusion medium at a storage temperature between about 0 and about 10 °C for shipping purposes. In this regard, one of ordinary skill in the art would be informed by the formulation stability teachings of Hollyman that a buffer system comprising plasmalyte + 1% HSA maintains the viability of a predominately CD4+, Th1 type T cell population from 70% to nearly 80% after 72 hours at 4 °C.
Thus, it would have been obvious to one of ordinary skill in the art that the formulation buffer comprising plasmalyte and HSA described by both Har-Noy and Hollyman would be suitable for formulating a biological drug composition comprising the CD4+, Th1 type T cells of Har-Noy, wherein said cells are to be stored between about 0 and about 10 °C for up to three days in a temperature controlled device, like the endurotherm package, that maintains the cells at the storage temperature so that said cells could be shipped and distributed to the point of care.
As to claim 2, given that Har-noy teaches their “T-cells and associated cross-linking biodegradable microspheres are suspended at a cell density of 107 cells/ml or greater in a flexible container or in a syringe” (see Har-Noy paragraph 43), it further would have been obvious to transport the formulated cells of Har-Noy in such a format for ease of manipulation and/or administration at the point of care.
Thus, 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, as evidenced by the references, especially in the absence of evidence to the contrary.
No claims are allowed.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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