Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 Mar 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-12 filed 19 Dec 2024 are originally presented and under consideration.
Claim Objections
Claim 6 is objected to because of the following informalities:
The phrase "low speed of centrifuge" recited in claim 6 line 3 is grammatically incorrect. The phrase "low speed centrifugation" is recommended.
Appropriate correction is required.
Specification
The use of the terms Spectra Optia®, Terumo BCT®, IceCube®, Minitube®, Gibco®, AIM-V®, CellGenix®, FACSCanto®, BD®, Becton Dickinson®, BioTek®, Sartorius®, and ATCC® which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology, be capitalized wherever they appear and, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
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.
Claim 6 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The phrase "independently accompanied" recited in claim 6 lines 2-3 is self-contradictory. It is unclear whether the step of thawing the PBSC "at a second temperature about 0 to 5 °C" is meant to perform as an independent, i.e., separate, step or to be performed accompanied by, i.e.. at the same time, as low speed centrifugation. Therefore, the metes and bounds of the claim are unclear, rendering the claim indefinite. To promote compact prosecution, claim 6 is interpreted as follows based on par. 15 of the specification:
"The method of claim 1, wherein prior to step (a), the cryopreserved PBSC stock is thawed at a first temperature of about 37 °C, then at a second temperature of about 0 °C to about 5 °C accompanied by a low speed centrifugation until the cryopreserved PBSCs are thawed."
The term “low” in claim 6 line 3 is a relative term that renders the claim indefinite. The term “low” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Furthermore, there is no outcome or effect of the centrifugation step by which a skilled artisan could determine whether a given centrifugation speed is sufficiently low. Therefore, the metes and bounds of the claim are uncertain.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. § 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2 and 9 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Pogue-Caley (US 8,153,425 B2, 2012).
Regarding claim 1, Pogue-Caley discloses a method of producing mature dendritic cells (DC) comprising the following steps: 1) isolation of peripheral blood mononuclear cells (PBMC) from healthy patients via leukapheresis and separation of the mononuclear fraction by Ficoll® density gradient centrifugation (isolated from a leukocyte concentrate, line 9), 2) culturing the PBMC in a medium comprising granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 4 (rIL-4) to generate immature dendritic cells (cultivating medium comprising GM-CSF and IL-4 to produce immature DC, step (a)), and 3) treating the immature dendritic cells with a maturation medium comprising GM-CSF, IL-4, tumor necrosis factor (TNFα), and prostaglandin E2 (PGE2) generate mature DC (cultivating medium supplemented with GM-CSF, IL-4, TNFα, and PGE2 to produce mature dendritic cells, step (b)) (Abstract and Example 1 col. 25 lines 23-52 and col. 26 lines 38-42).
Regarding claim 2, the method disclosed by Berger comprises isolation of fresh PBMC from healthy patients via leukapheresis (Example 1 col. 25 lines 23-37). Note that a limiting definition for the term "freshly" is not provided in the immediate specification. Therefore, under the broadest reasonable interpretation, claim 2 is construed to mean that PBMC are isolated from a leukocyte concentrate and cultured prior to cryopreservation.
Regarding claim 9, the enrichment medium comprises 800 U/mL GM-CSF and 500 U/mL rIL-4, a ratio of 1.6:1.0 (within the claimed range of about 1:1 to 2:1 by unit) (Example 1 col. 25 lines 47-50).
Claims 1-2 and 9 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by Berger (T.G. Berger, et al., J Immunol Methods, 2002).
Regarding claim 1, Berger discloses a method of producing mature dendritic cells (DC) comprising the following steps: 1) isolation of peripheral blood mononuclear cells (PBMC) from healthy patients via leukapheresis (isolated from a leukocyte concentrate, line 9), 2) treating the PBMC with an enrichment medium comprising granulocyte-macrophage colony stimulating factor (GM-CSF) and recombinant human interleukin 4 (rIL-4) to generate immature dendritic cells (cultivating medium comprising GM-CSF and IL-4 to produce immature DC, step (a)), and 3) treating the immature dendritic cells with a maturation medium comprising GM-CSF, IL-4, tumor necrosis factor (TNFα), and prostaglandin E2 (PGE2) generate mature DC (cultivating medium supplemented with GM-CSF, IL-4, TNFα, and PGE2 to produce mature dendritic cells, step (b)) (Abstract and Materials and Methods §§ 2.1-2.2 pp. 132-133).
Regarding claim 2, the method disclosed by Berger comprises isolation of fresh PBMC from healthy patients via leukapheresis (Materials and Methods § 2.1, p. 132).
Regarding claim 9, the enrichment medium comprises 800 U/mL GM-CSF and 500 U/mL rIL-4, a ratio of 1.6:1.0 (within the claimed range of about 1:1 to 2:1 by unit) (Materials and Methods § 2.2 p. 133).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. § 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-6 and 9 are rejected under 35 U.S.C. § 103 as being unpatentable over Pogue-Caley (US 8,153,425 B2, 2012) as applied to claims 1-2 and 9 above, and further in view of Spoerl (S. Spoerl, et al., Springer, 2016) and Clarke (D.M. Clark, et al., Cytotherapy, 2009).
Pogue-Caley discloses a method for producing mature dendritic cells (DC) from peripheral blood mononuclear cells (PBMC) as discussed in the rejection of claims 1-2 and 9 under 35 U.S.C. § 102(a)(1) above.
Pogue-Caley does not teach isolating PBMC from a cryopreserved stock or a specific cryopreservation procedure for the PBSC stock as required by claims 3-5.
Regarding claim 3, Pogue-Caley further teaches that the PBMC may be isolated from peripheral blood stem cells (PBSC) (col. 16 lines 4-13). Pogue-Caley further teaches that PBMC may be frozen or cultured soon after isolation from a subject (col. 1 lines 26-34). Pogue-Caley further teaches that monocytes may be frozen using a controlled rate freezer (col. 17 lines 17-44).
Regarding claims 3-4, Spoerl teaches that cryopreservation of PBSC provides flexibility for repeated transplantations and flexibility with patient schedules (§ 6.1 p. 69). Spoerl teaches that once PBSC are collected, they are mixed dimethyl sulfoxide (DMSO, mixing freshly isolated PBSC with an antifreeze, claim 3, line 2) and frozen at a controlled rate for storage up to several years (produce a PBSC stock, claim 3, line 2) (§ 6.2, p. 69). Spoerl teaches that controlled-rate freezing is performed using programmable sequences that usually start at about 2 °C (about 4 °C, claim 3 step (ii) line 4 and claim 4 step (i) (§ 6.4 p. 69). Spoerl further teaches that the typical freezing program would proceed stepwise (claim 4 line 1) until reaching the final temperature (§ 6.3 p. 69). Spoerl further teaches that the freezing rate influences recovery of white blood cells (such as PBSC) and that the optimal cooling rate varies by cell type (§ 6.3 p. 70).
Regarding claims 3-4, Clarke teaches a stepwise controlled freezing program for PBSC (Abstract and Methods p. 474). The steps comprise 1) cooling at 1 °C/min until heat of fusion, around - 5 °C to - 10 °C (near - 7 °C, claim 4 step (i)) and holding until the liquid freezes, 2) cooling at 1 °C/min until - 40 °C (about - 45 °C, claim 4 step (iii)), and 3) cooling at 10 °C/min until - 90 °C (about – 95 °C and a 50 °C change over 5 min, claim 4 step (iv)) (Methods p. 474).
Regarding claim 5, Spoerl teaches that PBSC stock may be stored in liquid nitrogen (§ 6.3 p. 69).
Regarding claim 6, Clarke teaches thawing cryopreserved PBSC by thawing at a first temperature just until ice crystals disappear followed by centrifugation at room temperature (second temperature accompanied by low speed centrifugation) (Methods p. 474).
As discussed above in the rejection of claim 6 under 35 U.S.C. § 112(b), a limiting definition for the term "low" is not provided in the immediate specification. Therefore, under the broadest reasonable interpretation, claim 6 is construed to mean that the centrifugation speed is low enough for centrifugation of PBMC without cell lysis.
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%). Where the temperature and rate of a process can be varied and result in the same properties, the claimed range(s) are patentably indistinct from the prior art. In the present case, Clarke successfully freezes PBSC using a patentably indistinct controlled freeze program and completes thawing at room temperature. Furthermore, "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). See MPEP § 2144.05.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the method of generating mature DC from fresh PBSC as taught by Pogue-Caley with cryopreserving the PBSC at a controlled rate prior to differentiation as taught by Spoerl and Clarke to arrive at the claimed invention. One would be motivated to make such a combination as Pogue-Caley suggests generating mature DC from PBSC or from cryopreserved precursors and suggests cryopreserving such cells by controlled rate freezing and as Spoerl teaches cryopreservation of PBSC is a routine procedure that allows for flexibility between harvesting cells and transplanting the cells. One would have a reasonable expectation of success in making the combination as Clarke teaches cryopreservation of PBSC using a patentably indistinct stepwise freezing protocol and as discovery of optimal conditions is routine procedure in the art.
Claims 1-2 and 8-9 are rejected under 35 U.S.C. § 103 as being unpatentable over Pogue-Caley (US 8,153,425 B2, 2012) as applied to claims 1-2 and 9 above, and further in view of Ichim (US 2021/0393681 A1, 2021) and Iscove (N.N. Iscove and F. Melchers, J Exp Med, 1978).
Pogue-Caley discloses a method for producing mature dendritic cells (DC) from peripheral blood mononuclear cells (PBMC) as discussed in the rejection of claims 1-2 and 9 under 35 U.S.C. § 102(a)(1) above.
Pogue-Caley does not teach a cultivating medium comprising salts, saccharides, amino acids, vitamins, transferrin, albumin, and insulin as required by claim 8.
Pogue-Caley further teaches that the cultivation medium for generating immature DC from PBMC used StemSpan™ H2000 medium as the basal medium in Example 1 (col. 25 lines 37-43). Pogue-Caley further teaches that enriched monocytes may be differentiated into dendritic cells in any suitable medium that comprises GM-CSF and IL-4 (cultivating medium, claim 8) (col. 18 lines 12-17).
However, Ichim teaches a method of generating mature DC from PBMC by culturing in a medium comprising GM-CSF and IL-4 (Abstract and par. 297). Ichim further teaches that in one embodiment, PBMC may be cultured in a medium comprising Iscove's modified Dulbecco's medium (IMDM) supplemented with insulin, human transferrin, and bovine serum albumin (par. 297).
IMDM comprises the salts sodium chloride, potassium chloride, calcium chloride, sodium pyruvate, and sodium selenite; glucose (a saccharide); all essential and non-essential amino acids; and the vitamins biotin, choline, pantothenate, folate, niacinamide, pyridoxine, riboflavin, thiamine, and cyanocobalamin (Iscove Materials and Methods p. 924). Iscove teaches generation of the medium to eliminate the need for use of serum in cell culture medium for immune cells as serum is highly variable and poorly defined, which "creates problems of reproducibility" and makes it difficult to "interpret and isolate the significance of biological activities released by the cells into the culture medium" (p. 923).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to substitute the basal medium for cultivating PBMC to differentiate into immature DC as taught by Pogue-Coley for IMDM supplemented with insulin, transferrin, and albumin as taught by Ichim and Iscove to arrive at the claimed invention. One would be motivated to make the substitution as Pogue-Coley teaches that the basal medium for generating immature DC from PBMC and as Iscove teaches that using a chemically defined medium without serum increases reproducibility. One would have a reasonable expectation of success in making the substitution as Pogue-Coley teaches that basal media are interchangeable so long as GM-CSF and IL-4 are added to the medium.
Claim 7 is rejected under 35 U.S.C. § 103 as being unpatentable over Pogue-Caley (US 8,153,425 B2, 2012), Ichim (US 2021/0393681 A1, 2021), and Iscove (N.N. Iscove and F. Melchers, J Exp Med, 1978) as applied to claims 1-2 and 8-9 above, and further in view of Rudin (A. Rudin, et al. Appl Microbiol, 1970).
Pogue-Caley, Ichim, and Iscove teach a method for producing mature dendritic cells (DC) from peripheral blood mononuclear cells (PBMC) as discussed in the rejection of claims 1-2 and 8-9 under 35 U.S.C. § 103 above.
Ichim further teaches that in one embodiment, the medium comprising IMDM, GM-CSF, and IL-4 may be supplemented with penicillin and streptomycin sulfate (par. 297). IMDM comprises L-glutamine (Materials and Methods p. 924).
Pogue-Caley, Ichim, and Iscove do not teach addition of gentamicin sulfate as required by claim 7.
However, Rudin teaches that gentamicin sulfate is a more effective antibiotic in cell culture than penicillin and streptomycin (p. 989). Rudin teaches that gentamicin has broad efficacy against gram-positive and gram-negative bacteria and mycoplasma and is bactericidal against a broader range of species than penicillin and streptomycin (p. 989). Rudin demonstrates in a similar cell culture system as Pogue-Caley, Ichim, and Iscove comprising mammalian cells and a cell culture medium that gentamicin can inhibit growth of 13 out of 14 bacterial species that are common cell culture contaminants, whereas the combination of penicillin and streptomycin without gentamicin can only inhibit growth of 4 out of 14 species (pp. 989-990 and Table 1).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to improve the method for generating immature DC from PBMC using a medium comprising penicillin and streptomycin as taught by Pogue-Caley, Ichim, and Iscove by supplementing the cell culture medium with gentamicin sulfate as taught by Rudin to arrive at the claimed invention. One would be motivated to make such an improvement as Rudin teaches that gentamicin is a more potent and effective antibiotic for preventing cell culture contamination than penicillin and streptomycin. One would have a reasonable expectation of success in making the improvement as Rudin demonstrates that gentamicin is a more effective inhibitor of bacterial culture in an analogous mammalian cell culture system.
Claims 1-2 and 9-11 are rejected under 35 U.S.C. § 103 as being unpatentable over Berger (T.G. Berger, et al., J Immunol Methods, 2002) as applied to claims 1-2 and 9 above and in further view of Eljaafari (A. Eljaafari, et al., Hum Immunol, 1998).
Berger discloses a method for producing mature dendritic cells (DC) from peripheral blood mononuclear cells (PBMC) as discussed in the rejection of claims 1-2 and 9 under 35 U.S.C. § 102(a)(1) above.
Berger does not teach supplementation with serum as required by claims 10-11.
Berger further teaches that the media for generating mature DC from PBMC further comprise the basal medium RPMI 1640 and heat inactivated autologous human plasma (Materials and Methods § 2.1 p. 132).
However, Eljaafari teaches a similar cultivation medium for generating immature DC from PBMC as Berger comprising RMPI 1640 as a basal medium, recombinant human GM-CSF, and recombinant human IL-4 (Materials and Methods p. 626). Eljaafari teaches that addition of human AB serum or human plasma, both heat-inactivated, are equally effective in generating mature DC from PBMC (Results p. 630 and Table 2).
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to substitute plasma in the medium for generating DC from PBMC as taught by Berger for serum as taught by Eljaafari to arrive at the claimed invention. One would be motivated to make such a substitution as Eljaafari teaches that autologous human serum and plasma are interchangeable. One would have a reasonable expectation of success in making the combination as Eljaafari demonstrates that in a highly similar base medium comprising RPMI 1640, GM-CSF, and IL-4, serum and plasma had indistinguishable effects in maturation of PBMC into DC.
Claims 1-2, 9, and 12 are rejected under 35 U.S.C. § 103 as being unpatentable over Pogue-Caley (US 8,153,425 B2, 2012) as applied to claims 1-2 and 9 above.
Pogue-Caley discloses a method for producing mature dendritic cells (DC) from peripheral blood mononuclear cells (PBMC) as discussed in the rejection of claims 1-2 and 9 under 35 U.S.C. § 102(a)(1) above.
Pogue-Caley does not teach ratio of 1:1:1 for IL-4, GM-CSF, and TNFα in the maturation medium as required by claim 12.
Pogue-Caley further teaches concentrations of 500 U/mL IL-4, 800 U/mL GM-CSF, and 10 ng/mL TNFα in the maturation medium to produce mature DC (Example 1 col. 26 lines 38-43). Pogue-Caley further teaches that the concentrations of cytokines can be varied for the maturation of PBMC to mature DC and that the concentration of GM-CSF can range between 800 and 1000 U/mL and IL-4 can range between 500 and 1000 U/mL (col. 2 lines 22-33).
However, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."). In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934) (the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical). Where the proportions of components in a composition can be varied and result in the same properties, the claimed range(s) are patentably indistinct from the prior art. In the present case, Pogue-Caley successfully generated mature DC using the same cytokines exemplified at slightly different concentrations or reported in different units. Furthermore, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See MPEP § 2144.05.
Therefore, it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to improve the method for generating mature DC from PBMC as taught by Pogue-Caley to arrive at the claimed invention. One would be motivated to make such a combination as Pogue-Caley teaches that the cytokine cocktail can be optimized and as discovery of optimal conditions is routine in the art. One would have a reasonable expectation of success in making the combination as Pogue-Caley generated mature DC using a patentably indistinct concentrations of IL-4, GM-CSF, and TNFα.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric B Wright whose telephone number is (571) 272-2607. The examiner can normally be reached Mo - Fr, 09:00 a.m. - 05:00 p.m. Eastern. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant may use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Eric B Wright, PhD
Examiner
Art Unit 1632
/Eric B Wright/Examiner, Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
Prosecution Insights