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 .
Priority
Acknowledgement is made that the instant application is a National Stage of International application No. PCT/US2023/07683 (filed 08/22/2023), which claims the benefits of US Provisional Application No. 63/400,382 (filed 08/23/2022).
Information Disclosure Statement
At least one of the references listed in the information disclosure statement filed 05/04/2025 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. Specific references “lined through” have not been considered.
Specification
The specification is objected to because Tables 6 and 7 have shading. The specification cannot contain any shading. Appropriate correction is required.
Claim Objections
Claims 2, 3, 6, and 59 are objected to because of the following informalities:
Claims 2, 3, and 6 recite the abbreviation DMSO without defining the full term. The full term should precede the first appearance of an abbreviation.
Claim 59 recites the abbreviation GS2 without defining the full term. The full term should precede the first appearance of an abbreviation.
Appropriate correction is required.
Claim Interpretation
Claim 35 is drawn to a method of treating a subject having a disorder or condition, comprising thawing the cell preparation of claim 31…. The claim is being interpreted as first comprising a step of providing the cell preparation of claim 31.
Claim Rejections - 35 USC § 112(a)
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.
Claim 35 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 35 is drawn to a method of treating a subject having a disorder or condition by administering a cryopreserved cell preparation. The specification, while being enabling for treating ocular diseases and disorders which benefit from administration of retinal pigment epithelium (RPE) cells, photoreceptor rescue cells, photoreceptor progenitor cells, or corneal endothelial cells, does not reasonably provide enablement for treatment of any disease or disorder. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to carry out the invention commensurate in scope with these claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Claim 32 recites treatment of “a disease or disorder”; the breath of the claims thus covers every disease and every disorder possible. Thus scope of the claims thus covers diseases or disorders characterized by tissue loss or damage (i.e. wounds to the epidermis, degenerated cartilage, organs which have suffered physical damage), diseases characterized by insufficient tissue (i.e. diabetes mellitus), diseases or disorders characterized by hyperproliferation of tissue (i.e. tumors), diseases or disorders characterized by aberrant immune response (i.e. auto-immune disorders), infections (bacterial, fungal, viral), genetic disorders, psychological disorders and diseases (i.e. schizophrenia, bi-polar disorder, depression), and more. Any and all diseases and disorders are covered by the claims. The claims do not limit the scope of the disease and/or disorders as having any common symptom, etiology, or mechanism (known or unknown). The breadth of the claims is thus extremely broad.
The nature of the invention is cell-based therapies. While the claims do not limit the type of cells used in the method, the specification only discloses cell preparations comprising RPE cells, photoreceptor rescue cells, and corneal endothelial cells. RPE cells, photoreceptor rescue cells, and corneal endothelial cells were well known and generally well characterized at the time the invention. While the basis of cell-based therapies was well-known at the time the invention was made, due to the complex interactions which occur between the therapeutic cells and the complex human body and lack of understanding of the exact mechanisms of action of specific cells, it was still considered a highly complex field.
The artisan of ordinary skill would be one having an advanced degree in cell biology and/or significant experience in studying ocular cell types. One may have experience in clinical trials, per se, but would at least have extended knowledge regarding assaying the effects of ocular cells when administered to a subject.
At the time the invention was made RPE cells were being tested as a cell-based therapy for the treatment of age-related macular degeneration and Stargardt disease (See Raimondi et al (Int. J. Mol. Sci, 2022), Secs: 2.1, 2.2, and 2.3); corneal epithelial cells were being investigated for treatment of corneal endothelial disease (e.g. corneal dystrophy) (See Faye (Experimental Eye Research, 2021), abstract); and photoreceptor cells were being investigated as a therapy for photoreceptor degenerative diseases (See Gagliardi et al (Progress in Retinal and Eye Research, 2019), abstract). Thus administration of RPE cells, photoreceptor rescue cells, and corneal endothelial cells was not known to be a treatment of all diseases or disorders . There was no evidence at the time the invention was made that RPE cells, photoreceptor rescue cells, and corneal endothelial cells would have any effect on infections, non-ocular genetic disorders, or psychological diseases or disorders. There was no known link between, at least these types of diseases and disorders and RPE cells, photoreceptor rescue cells, and corneal endothelial cells. None of the known effects of RPE cells, photoreceptor rescue cells, and corneal endothelial cells would have been expected to have an effect on the underlying causes or symptoms of infections, non-ocular genetic disorders or psychological diseases or disorders.
The examples provided in the specification only teach the effects of cryopreservative formulations on RPE cells, photoreceptor rescue cells, and corneal endothelial cells but do not exemplify treatment methods using the cells.
In total, the specification and prior art support RPE cells, photoreceptor rescue cells, and corneal endothelial cells can be to treat ocular diseases and disorders, one would not have a reasonable expectation of successfully treating any disease or disorder. The scope of the claims is beyond what was known/expected based on the prior art, and taught in the instant specification.
Claim Rejections - 35 USC § 112(b)
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.
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 27 and 59 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 27 recites the limitation "the vial, syringe, ampoule, bottle or cooler package" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 59 recites the diluents is GS2 or GS2 Plus. The specification states GS2 and GS2 Plus are described in WO2017031312A1 (See ¶00131). WO2017031312A1 discloses the composition of GS2 medium in Example 1 but does not disclose the composition of GS2 Plus including optional components (See ¶00141-00143). WO2024044134A1 discloses two compositions for GS2 and GS2 Plus mediums (See ¶532-534 and Table 5). The two compositions of GS2 disclosed in WO2024044134A1 do not have the same formulations. No additional information regarding a formulation of GS2 Plus was found. Given that GS2 can comprise a medium with various formulations and GS2 Plus is not a common name for a medium used in the art, the meets and bounds of a diluent comprising ‘GS2’ or ‘GS2 Plus’ is undefined.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 9, 19, 22-23, 31-32, 47, and 58 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lionetti et al (Cryobiology, 1980) as evidenced by Pubchem (D-glucose page).
Lionetti et al discloses cryopreserving granulocytes at a concentration of 3 x 107 in 2.0 ml volumes in 17 x 100 mm polypropylene tubes (See pg. 309, Summary and pg. 298, Sec. Cryopreservation of granulocytes). The granulocytes were cryopreserved in a solution comprising 5% DMSO, 6% HES, 4% human serum albumin, and 0.056 M glucose in Normosol-R (See pg. 298 first column, Sec. Cryopreservation of granulocytes and pg. 309, Sec. Summary). Lionetti et al further discloses thawing the granulocytes in a 42° C water bath until a 3 mm pellet remained; swirling the tubes and placing the tubes in an ice water bath; then diluting the cells 1:4 by dropwise addition of a room temperature solution comprising 7% HES, 4% human serum albumin, and 28 mM glucose in Normosol-R (See pg. 298, Sec. Thawing and washing).
Regarding claims 1-3: Lionetti et al discloses a solution comprising 5% DMSO (reads on about 4-10% cryoprotectant), 4% albumin (reads on about 2-8% albumin), and 0.056 M glucose in NormosolR (reads on a buffer). Glucose has a molecular weight of 180.16 g/mol (See PubChem). Thus the solution of Lionetti et al comprises 1.009% glucose (% w/v = (0.056 mol/L x 180.16 g/mol) / 10) which reads on about 0-1.5% glucose.
Regarding claim 4: Following the discussion of claim 1 above, the solution of Lionetti et al comprise 5% DMSO which reads on 4-6% cryoprotectant.
Regarding claim 9: Following the discussion of claim 1 above, Lionetti et al discloses using human serum albumin which reads on human albumin.
Regarding claim 19: Following the discussion of claim 1 above, Lionetti et al discloses cryopreserving a composition comprising granulocytes in the cryoprotective solution. Given that the cryoprotective solution is cryopreserved with the cells, the cryoprotective solution of Lionetti et al is cryopreserved.
Regarding claim 22: Lionetti et al discloses cryopreserving granulocytes (reads on a population of cells) in a solution comprising 5% DMSO, 4% albumin, and 0.056 M glucose in NormosolR. The solution of Lionetti et al reads on the formulation of claim 1 (See rejection of claim 1 above). The granulocytes in the solution thus read on the claimed cell preparation.
Regarding claim 23: Following the discussion of claim 22 above, Lionetti et al discloses cryopreserving granulocytes at a concentration of 30 x 106 – 50 x 106 in 2.0 ml volumes which is equivalent to 15,000 – 25,000 cells/µL which reads on about 10,000 -100,000 cells/µL.
Regarding claim 31: Following the discussion of claim 22 above, Lionetti et al discloses cryopreserving the granulocytes in the cryoprotective solution which reads on the cell preparation is cryopreserved.
Regarding claim 32: Lionetti et al discloses cryopreserving granulocytes (reads on a population of cells) in a solution comprising 5% DMSO, 4% albumin, and 0.056 M glucose in NormosolR. The solution of Lionetti et al reads on the formulation of claim 1. Given that the cells are cryopreserved in the solution, the cells are necessarily contacting the solution. Thus, Lionetti et al discloses a method of preparing a cell preparation comprising contacting the formulation of claim 1 with a cell population.
Regarding claim 47: , Lionetti et al discloses cryopreserving granulocytes in a cryoprotective solution which reads on the cell preparation of claim 31. Lionetti further discloses thawing the cryopreserved granulocytes by immersing tubes in a water bath followed by swirling. The thawed granulocytes were then diluted 1:4 (reads on 1:2 to 1:20), in a solution comprising 7% HES, 4% human serum albumin, and 28 mM glucose in Normosol-R which reads on a pharmaceutical composition suitable for administration to a subject.
Regarding claim 58: Following the discussion of claim 31 above, Lionetti et al discloses a thawing method comprising thawing cells until a 3 mm ice pellet remains, swirling the tubes and placing them in an ice water bath, and adding a room temperature solution dropwise to dilute the cells 1:4. Thus, the thawing method of Lionetti et al comprises a step of thawing from an ice bath to room temperature by dilution with a diluent. Furthermore, Lionetti et al does not disclose a step of washing thus the cells are unwashed.
Claims 1-4, 9, 19, 22-23, 27, 31-32, and 34 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li et al (CN112544612A).
Li et al discloses a freezing solution comprising 0-10 parts DMSO solution, 10-30 parts human serum albumin solution, 0-10 parts glucose solution, 4-8 parts hydroxyethyl starch solution, 10-30 parts dextran 40 solution, 0-4 parts vitamin C solution, and a solvent selected from physiological saline, culture medium, sterile water and a sterile buffer solution (See pgs. 1-2 of Li et al, English translation). The mass volume percentage of DMSO in the DMSO solution is greater than 99.9% (See pg. 2 of Li et al, English translation). The mass volume percentage of human albumin in the human albumin solution is 20% (See pg. 2 of Li et al, English translation). The mass volume percentage of glucose in the glucose solution is 50% (See pg. 2 of Lie et al, English translation). In one embodiment, the freezing solution comprises 5 parts of DMSO (See pg. 3 of Li et al, English translation). The solution freezing solution of Li et al was used to cryopreserve RPE cells (See pg. 4, of Lit et al English translation, Sec. Detailed ways). P2 RPE cells were resuspended in freezing medium at a cell density to 6.0×106 cells/mL, and 1.5×106 cells were distributed per tube into labeled 2mL cryopreservation tubes (See pg. 5, of Lit et al English translation, Step 4. Cryopreservation of P2 generation cells). Lit et al discloses a step of thawing cells in a water bath with continuous shaking until few ice crystals exist, then rapidly transferring the cells into a culture medium that is 9 times the volume of the cryoprotective solution (See pg. 5, of Lit et al English translation, Step 1). Li et al further discloses a cell preparation comprising RPE cells and cryopreservation solution as a medicine for the treatment of retinal related diseases (See claims 7-10).
Regarding claims 1-3: Li et al discloses a freezing solution comprising 0-10 parts of a >99.9% DMSO solution (reads on a cryoprotectant), 10-30 parts of a 20% human serum albumin solution, 0-10 parts of a 50% glucose solution and a sterile buffer solution. The freezing solution of Li et al thus comprises 0-9.9% DMSO (reads on 4-10% cryoprotectant), 2-6% human serum albumin (reads on 2-8% albumin), and 0-5% glucose (reads on 0-1.5% glucose).
Regarding claim 4: Following the discussion of claim 1 above, Li et al discloses an embodiment in which the solution comprises 5 parts of the >99.9% DMSO solution and thus about 5% DMSO which reads on about 4-6% cryoprotectant.
Regarding claim 9: Following the discussion of claim 1 above, the freezing solution of Li et al comprises human serum albumin which reads on human albumin.
Regarding claim 19: Following the discussion of claim 1 above, Li et al discloses cryopreserving cells in the freezing solution, thus the freezing solution is necessarily cryopreserved.
Regarding claim 22: Li et al discloses a freezing solution comprising 0-9.9% DMSO, 2-6% albumin, 0-5% glucose, and a sterile buffer which reads on the formulation of claim 1. Li et al further discloses a cell preparation comprising RPE cells and the freezing solution which reads on the cell preparation of the instant claim.
Regarding claim 23: Following the discussion of claim 22 above, Li et al discloses the cell preparation comprises RPE cells which reads on (iii) of the instant claim.
Regarding claim 27: Following the discussion of claim 22 above, Li et al discloses resuspending cells in the freezing medium at a concentration of 6.0×106 cells/mL then distributing 1.5×106 cells into each 2 mL freezing tube (reads on a vial). 1.5×106 cells at a concentration of 6.0×106 cells/mL is equivalent to 250 µL of the cell preparation which reads on about 10 to about 500 µL of preparation per vial.
Regarding claims 31 : Following the discussion of claim 22 above, Li et al discloses cryopreserving RPE cells resuspended in the freezing solution which reads on the cell preparation is cryopreserved.
Regarding claims 32 and 34: Li et al discloses a freezing solution comprising 0-9.9% DMSO, 2-6% albumin, 0-5% glucose, and a sterile buffer which reads on the formulation of claim 1. Li et al further discloses a resuspending RPE cells in the freezing solution which reads on a method of preparing the cell preparation comprising contacting a formulation of claim 1 with a population of cells.
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.
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 1-4, 9, 19, 22-23, 27, 31-32, 47, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Lionetti et al (Cryobiology, 1980) as evidenced by Pubchem (D-glucose page).
The teachings of Lionetti et al Pubchem are set forth above.
Lionetti et al, evidenced by Pubchem, anticipates claims 1-4, 9, 19, 22-23, 31-32, 47, and 58.
Regarding claim 27: Following the discussion of claim 22 above, Lionetti et al discloses granulocytes in a cryopreservation solution which reads on the cell preparation of claim 22. Lionetti et al further discloses adding 2.0 ml volumes of the cell preparation in 17 x 100 mm polypropylene tubes (reads on a vial).
Lionetti et al does not disclose about 10 to about 500 µL of the cell preparation are in a vial.
Although Lionetti et al does not disclose vials comprising about 10 to about 500 µL of the cell preparation, it would have been prima facie obvious to a person of ordinary skill in the art to optimize the volume of cell preparation added to a vial, and arrive at the claimed volume of about 10 to about 500 µL through routine experimentation, based on the size of vials used to store the cell preparation. The size of vial used for storage could be affected by various factors including available space in a liquid nitrogen (LN2) tank and the type of racks/boxes used for storage in the LN2 tank. Where 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. See MPEP2144.05(II).
Claims 1-6, 9, 19, 22-23, 27, 31-32, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN112544612A).
The teachings of Li et al are set forth above.
Li anticipates claims 1-4, 9, 19, 22-23, 27, 31-32, and 34.
Regarding claim 5: Following the discussion of claim 1 above, Li et al discloses a freezing solution comprising 0-9.9% DMSO, 2-6% albumin, 0-5% glucose, and a sterile buffer. Claim 5 of the instant application is drawn to a formulation comprising 0.08%-0.10% glucose. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists (See MPEP2144.05(I); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976): In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)). In the instant case because the prior art range overlaps the claimed range a prima facie case of obviousness exists.
Regarding claim 6: Following the discussion of claim 1 above, Li et al discloses a freezing solution comprising 0-9.9% DMSO, 2-6% albumin, 0-5% glucose, and a sterile buffer. In one embodiment the solution comprises about 5% DMSO. The specification of the instant application does not define the term “about” thus, the 2% albumin in the solution of Li et al reads on about 2.5% albumin and the 0% glucose reads on about 0.09%.
Claims 1-6, 9, 19, 22-23, 27, 31-32, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN112544612A) in view of Best (Rejuvenation Res. 2015) Erol et al (World Journal of Stem Cells, 2021).
The teachings of Li et al are set forth above.
Li anticipates claims 1-4, 9, 19, 22-23, 27, 31-32, and 34 and renders claims 1-6, 9, 19, 22-23, 27, 31-32, and 34 obvious.
Further Regarding claim 6: Following the discussion of claim 1 above, Li et al discloses a freezing solution comprising 0-9.9% DMSO, 2-6% albumin, 0-5% glucose, and a sterile buffer. In one embodiment the solution comprises about 5% DMSO. The 2% albumin in the solution of Li et al reads on about 2.5% albumin and the 0% glucose reads on about 0.09%.
Furthermore, Erol et al teaches albumin is used as a supplementary cryoprotective agent to coat surfaces, serves as a buffer, and has the capacity to bind hormones, growth factors, fatty acids, and metals.
Given that Li et al discloses cryopreserving cells in a solution comprising 2-6% albumin and Erol et al discloses albumin has the capacity to bind hormones, growth factors, fatty acids, and metals, it would have been prima facie obvious to optimize the concentration of albumin in the freezing solution of Li et al and arrive at the claimed concentration of 2.5% through routine optimization based on the presence of hormones, growth factors, fatty acids, and metals in the other components of the freezing solution. Where 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. See MPEP2144.05(II).
Best teaches glucose is used as an extracellular cryoprotective agent because of its low toxicity. However glucose has specific toxicities such as binding to proteins and causing glycation (See pg. 430, second column, paragraphs 1-3).
Given that Li et al discloses cryopreserving cells in a freezing solution comprising 0-5% glucose and Best teaches glucose can bind to proteins and cause glycation, it would have been prima facie obvious to optimize the concentration of glucose, in the freezing solution of Li et al and arrive at the claimed concentration of 0.09% or 0.6% through routine experimentation, in order to reduce the amount of glycation. Where 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. See MPEP2144.05(II).
Claims 1-6, 9, 11, 19, 22-23, 27, 31-32, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN112544612A) in view of Kuhn et al (WO2020023905A1)
The teachings of Li et al are set forth above.
Li anticipates claims 1-4, 9, 19, 22-23, 27, 31-32, and 34 and renders claims 1-6, 9, 19, 22-23, 27, 31-32, and 34 obvious.
Regarding claim 11: Following the discussion of claim 1 above, Li et al discloses a freezing solution comprising DMSO, glucose, albumin, and a buffer.
Li et al does not disclose the buffer is a buffered saline.
Kuhn et al discloses a composition comprising cells, a cryoprotectant, and a buffer (See claims 1 and 37). The buffer can comprise PBS or TBS (read on buffered salines).
Given that Li et al discloses a freezing solution comprising a cryoprotectant and a buffer and Kuhn et al discloses a composition comprising a cryoprotectant and a buffer wherein the buffer can comprise PBS or TBS, it would have been prima facie obvious to substitute the buffer of Li et al with the PBS or TBS of Kuhn et al, in the freezing solution of Li et al. One would have expected the PBS or TBS of Kuhn et al to work equivocally with the buffer of Li et al, in the method of Li et al because PBS and TBS are buffers that can be used with a cryoprotectant. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Claims 1-6, 9, 19, 22-23, 27, 31-32, 34-35, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN112544612A) in view of Gay et al (WO2017031312A1).
The teachings of Li et al are set forth above.
Li anticipates claims 1-4, 9, 19, 22-23, 27, 31-32, and 34 and renders claims 1-6, 9, 19, 22-23, 27, 31-32, and 34 obvious.
Regarding claims 35 and 47: Li et al discloses a cell preparation comprising RPE cells and freezing solution as a medicine for the treatment of retinal related diseases. The cell preparation of Li et al is prepared by resuspending cells in the freezing solution at a concentration of 6.0×106 cells/mL which is equivalent to 6000 cells/µL. Li et al further discloses a thawing step comprising thawing the cells in a water bath.
Li et al does not disclose diluting the cells or administering the cell preparation to a subject.
Gay et al discloses a method of treating a retinal disease comprising administering a cell preparation to a subject (See claim 41). The cell preparation of Gay et al comprises RPE cells in GS2 or BSS Plus at a concentration of 2000 to 2300 cells/µL (See ¶00165).
Given that Li et al and Gay et al both disclose cell preparations, comprising RPE cells and a freezing solution, which can be used to treat a retinal disease, and Gay et al further discloses the RPE cells should be administered at a concentration of 2000 to 2300 cells/µL, it would have been prima facie obvious to add a step of diluting the cells of Li et al to a final concentration of 2000 to 2300 cells/µL for use in the treatment method of Li et al. Diluting a preparation comprising 6000 cells/µL to a concentration of 2000 cells/µL would be achieved by diluting the cells at a ratio of 1:2. One would have been motivated to dilute the cells of Li et al in the treatment method of Li et al because Gay et al teaches cell preparations comprising 2000 to 2300 cells/µL can be used as a treatment for retinal disease. There is a reasonable expectation of success because Gay et al and Li et al both teach cell preparations comprising RPE cells for treatment of retinal disease.
Additionally, it would have been prima facie obvious to add a step of administering the diluted cells Li et al to a subject, in the treatment method of Li et al. One would have been motivated to add a step of administering the diluted cells to a subject in the treatment method of Li et al because Li et al discloses the cell preparation can be used as a treatment for a subject with retinal disease and treating a subject with the cells would require a step of administering the cells to the subject. There is a reasonable expectation of success because Gay et al teaches diluted cell preparations comprising RPE cells can be administered to a subject in a treatment method for retinal disease.
Claims 1-6, 9, 19, 22-23, 27, 31-32, 34 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN112544612A) in view of Barker et al (Biol Blood Marrow Transplant, 2009).
The teachings of Li et al are set forth above.
Li anticipates claims 1-4, 9, 19, 22-23, 27, 31-32, and 34 and renders claims 1-6, 9, 19, 22-23, 27, 31-32, and 34 obvious.
Regarding claim 58: Following the discussion of claims 22 and 31 above, Li et al discloses a cryopreserved cell population comprising RPE cells and a cryoprotective solution. Li et al further discloses thawing the cells in a water bath until few ice crystals remain then transferring the cells into a culture medium. Given that ice crystals remain in the cell preparation when the culture medium is added, the thawing method of Li et al comprises a step of thawing by dilution in a culture medium (reads on diluent). However, the method of Li et al further comprises a steps of centrifuging the cells and resuspending which reads on washing the cells. Li further discloses the cell preparation can be used as a treatment for retinal disease.
Barker et al teaches washes are used to remove DMSO. However, adults and larger pediatric recipients can tolerate small amounts of DMSO without clinically significant toxicity (See introduction). Barker et al further teaches thawing by dilution can be used to prepare cells for infusion in a “no wash” technique (See abstract and Introduction). The “no wash” technique is advantageous in that cell loss is minimized and the time to infusion is shortened (See introduction).
Given that Li et al discloses a cell preparation for treatment of retinal disease and Barker et al teaches cells for infusion can be thawed by dilution, it would have been prima facie obvious to modify the method of Li et al to include a thawing method which comprises thawing the cells by dilution and not washing the cells. One would have been motivated to modify thawing steps of Li et al because Barker et al teaches thawing using a “no wash” method reduces cell loss and shortens time to infusion. There is a reasonable expectation of success because Barker et al teaches cells can be thawed by dilution with a no wash method which results in a cell preparation that has small amounts of DMSO which are not toxic.
Claims 1-6, 9, 19, 22-23, 27, 31-32, 34-35, 47, and 58-59 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN112544612A) in view of Barker et al (Biol Blood Marrow Transplant, 2009) and Gay et al (WO2017031312A1).
The teachings of Li et al are set forth above.
Li et al anticipates claims 1-4, 9, 19, 22-23, 27, 31-32, and 34 and renders claims 1-6, 9, 19, 22-23, 27, 31-32, and 34 obvious.
Li et al and Barker et al anticipate claims 1-6, 9, 19, 22-23, 27, 31-32, 34 and 58
Li et al and Gay et al anticipate claims 1-6, 9, 19, 22-23, 27, 31-32, 34-35, and 47
Regarding claim 59: Following the discussion of claims 22, 31, and 58 above, Li et al discloses a cryopreserved population of RPE cells in a cryoprotective solution that can be used for the treatment of a retinal disorder. It would have been prima facie obvious to thaw the cells by dilution (See rejection of claim 58 above).
Li et al does not disclose the RPE cells are diluted GS2 or GS2 Plus.
Gay et al discloses a cell preparation for treatment of retinal disease comprising RPE cells diluted in GS2 medium.
Given that Li et al discloses a diluted population of RPE cells for treatment of retinal disease and Gay et al discloses a cell preparation comprising RPE cells in GS2 medium which can be used for treatment of retinal disease, it would have been prima facie obvious to substitute the diluent of Li et al with GS2 medium in the cell preparation of Li et al. One would have expected the GS2 medium to work equivocally with the diluent of Li et al because Gay et al discloses GS2 medium can be used to dilute RPE cells for cell preparations used in the treatment of retinal disease. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Claims 1-6, 9, 19-20, 22-23, 27, 31-32, 34, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al (CN114762499A) in view of Li et al (CN112544612A).
The teachings of Li et al are set forth above.
Li anticipates claims 1-4, 9, 19, 22-23, 27, 31-32, and 34 and renders claims 1-6, 9, 19, 22-23, 27, 31-32, and 34 obvious.
Zhu et al discloses a cryopreservation solution comprising 20-30 parts of human albumin solution, 4-8 parts of DMSO, 25-40 parts of mixed glucose injection, and 30-50 parts of a serum free basal medium (See pg. 1, English translation, Summary of the Invention). The mixed glucose injection comprises dextran 40 or glucose and sodium chloride (See pg. 1, English translation, Summary of the invention). The volume concentration of the human albumin solution is 20% (See pg. 3, English translation, 7th paragraph and pg. 4, Example 1). The glucose sodium chloride injection is a preparation comprising 8g glucose and 0.18g sodium chloride per 100mL of solution (See pg. 3, English translation, 15th paragraph). Zhu et al further discloses a cryopreservation process comprising digesting mesenchymal stem cells, pipetting to make the cells uniform, centrifuging the cells and discarding the supernatant, resuspending the cells in 2 ml of freezing solution, then cryopreserving the cells for 6 months (See pg. 6, English translation second to last paragraph). The cells were recovered by thawing in a water bath then diluting 5 fold with culture medium (See pg. 6, English translation, last paragraph).
Regarding claims 1-3: Zhu et al discloses a cryopreservation solution comprising 4-8 parts DMSO (reads on 4-10% cryoprotectant), 20-30 parts of a 20% human albumin solution, 25-40 parts of a mixed glucose solution comprising 8g glucose/mL and a serum free medium. 20-30 parts of a 20% human albumin solution is a concentration of 4-6% human albumin in the cryopreservation solution which reads on 2-8%. The glucose solution comprising 8 g/mL reads on an 8% solution. Thus, a cryopreservation solution comprising 25-40 parts of an 8% glucose solution comprises 2-3.2% glucose. The specification of the instant application does not define the term “about” thus, the cryopreservation solution of Zhu et al which can comprise 2% glucose reads on about 1.5% glucose.
Zhu et al does not disclose a cryopreservation solution comprising a buffer.
Li et al discloses a cryopreservation solution comprising DMSO, albumin, glucose, and a solvent (See pg. 3, of Li et al English translation). The solvent of Li et al is selected from a physiological saline, culture medium, sterile water, or a sterile buffer (See pg. 3, of Li et al English translation).
Given that Zhu et al and Li et al both disclose cryopreservation solutions comprising DMSO, albumin, and glucose, and Li et al further teaches culture medium and sterile buffers are an art recognized equivalent solvent for preparing a cryopreservation solution, it would have been prima facie obvious to substitute the serum free medium of Zhu et al with the sterile buffer of Li et al, in the cryopreservation of Zhu et al. One would have expected the sterile buffer of Li et al to work equivocally with the serum free medium of Zhu et al in the cryopreservation solution of Zhu et al, because Li et al teaches culture medium and sterile buffer are art recognized equivalent solvents that can be used for preparation of cryoprotective solutions. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable is considered to be obvious. See KSR International Co. V Teleflex Inc 82 USPQ2d 1385 (US2007) at page 1395.
Regarding claim 4: Following the discussion of claim 1 above, the cryoprotective solution of Zhu et al comprises 4-8 parts DMSO (i.e. 4-8% DMSO) which reads on 4-6% cryoprotectant.
Regarding claim 9: Following the discussion of claim 1 above, Zhu et al discloses the cryoprotective solution comprises human albumin.
Regarding claim 19: Following the discussion of claim 1 above, Zhu et al discloses cryopreserving mesenchymal stem cells in 2mL of cryoprotective solution. Thus the cryoprotective solution is necessarily cryopreserved.
Regarding claim 20: Following the discussion of claim 1 above, the cryoprotective solution of Zhu et al comprises DMSO, albumin solution, and glucose solution. In embodiments where the glucose solution comprises 8 mg glucose, 0.18 mg saline, and a solvent, the glucose solution does not comprise dextran. Additionally, Zhu et al does not disclose the formulation comprises a polymeric excipient.
Regarding claim 22: Zhu et al disclose a cryopreservation solution comprising DMSO, albumin, glucose, and serum free medium. It would be obvious to substitute the serum free medium with a sterile buffer (see rejection of claim 1 above). Zhu et al further discloses adding cryopreservation solution (reads on formulation of claim 1) to mesenchymal stem cells (reads on a population of cells) in order to cryopreserve the cells. Thus, Zhu et al discloses a cell preparation comprising the formulation of claim 1 and a population of cells.
Regarding claim 23: Following the discussion of claim 22 above, the mesenchymal stem cells in the cell preparation of Zhu et al comprise mesenchymal stem cells which were digested then pipetted to distribute the cells evenly which reads on a dissociated cell population.
Regarding claim 31: Following the discussion of claim 22 above, Zhu et al discloses cryopreserving the mesenchymal stem cells in the cryoprotective solution which reads on the cell preparation is cryopreserved.
Regarding claim 32: Zhu et al discloses a step of resuspending mesenchymal stem cells in a cryopreservation solution which reads on a method of preparing a cell preparation comprising contacting a formation of claim 1 with a population of cells.
Regarding claim 47: Zhu et al discloses a cryopreserved mesenchymal stem cell population in a cryoprotective solution which reads on the cryopreserved cell preparation of claim 31. Zhu et al further discloses thawing the cells and diluting the cells 5 fold in culture medium which reads on diluting the cell preparation in a diluent at a ratio in the range of 1:2 to 1:20 and wherein the pharmaceutical composition is suitable for administration to a subject.
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.
Claim 1-6, 9, 11, 19, 22-23, 31-32, and 34 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 1-133 of copending Application No. 19/619052 and
claims 1-304 of copending Application No. 19/099554
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 1 of the instant application recites a formulation comprising about 4-10% cryoprotectant, about 2-8% albumin, about 0-1.5% glucose, and a buffer. These limitations are taught by claim 249 of application ‘554 and claims 1-65 of application ‘052.
Claims 2 and 3 of the instant application require the cryoprotectant to be DMSO or ethylene glycol. This limitation is taught by claims 131 and 132 of ‘554 and claims 29-31 of ‘052.
Claims 4-6 further define specific concentrations of the cryoprotectant, glucose, and albumin. The same concentrations are disclosed in claims 133-137 of ‘554 and claims 61-64 of ‘052.
Claim 9 requires the albumin be human albumin. This limitation is disclosed in claim 139 of ‘554 and claim 3 of ‘052.
Claim 11 requires the buffer be a buffered saline. This limitation is taught in 140-141 of ‘554 and claim 116 of ‘052.
Claim 19 requires the formulation of claim 1 is cryopreserved. This limitation is taught in claim 144 of ‘554 and claim 113 of ‘052.
Claims 22 and 23 require a cell preparation comprising the formulation of claim 1 and a population of cells. Claim 130 of ‘554 discloses photoreceptor cells in the formulation of claim 1 and claim 103 of ‘052 discloses a cell preparation comprising dissociated cells, a cell sheet, etc. in the formulation of claim 1.
Claim requires the cell preparation is cryopreserved. This limitation is taught by 144 of ‘554 and claim 113 of ‘052.
Claim 32 requires contacting the formulation of claim 1 with a population of cells this limitation is taught by claim 130 of ‘554 and claim 103 of ‘052.
Claim 34 requires the cell population to be RPE cells, photoreceptor rescue cells, photoreceptor progenitor cells, or corneal endothelial cells. Claim 130 of ‘554 discloses photoreceptor cells in the formulation of claim 1 and claim 93 of ‘052 discloses a cell population comprising RPE cells, photoreceptor rescue cells, photoreceptor progenitor cells, or corneal endothelial cells.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/MARISOL ANN O'NEILL/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
