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 .
Claim Status
Claims 2-4, 6, 11-12, 14, and 28-37 have been canceled, claims 1, 5, 7-10, 13, and 15-27 are currently amended, claims 1, 5, 7-10, 13, and 15-27 have been considered on their merits.
Information Disclosure Statement
The listing of references in the PCT international search report is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, “the list ... must be submitted on a separate paper.” Therefore, the references cited in the international search report have not been considered. Applicant is advised that the date of submission of any item of information in the international search report will be the date of submission of the IDS for purposes of determining compliance with the requirements for the IDS with 37 CFR 1.97, including all timing statement requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 8 is objected to because of the following informalities: the term “Glycerol” should not be capitalized.
Claim 16 is objected to because of the following informalities: the term “Glycerol” should not be capitalized.
Claim 17-19 is objected to because of the following informalities: the terms “Glycerol” and “Dextran” should not be capitalized.
Claim 24 is objected to because of the following informalities: the term “Long-term” should not be capitalized.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 22, 24, and 26 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.
Regarding claim 22, the claim language is unclear. It is not clear whether viability post lyophilization is reduced to 0%, i.e., no viable cells remain or if the decline in viability post lyophilization from 70-100%, i.e., reduced by 0-30%. The claim will be interpreted as the viability post lyophilization has declined no more than about 0-30%.
The term “easy” in claims 24 and 26 is a relative term which renders the claim indefinite. The term “easy” 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. The specification does not establish to what standard "easy" can be determined.
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, 5, 7-8, 10, 13, and 20-27 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Huang et al. (CN106821938B, published 24 March 2020).
An English machine translation of the Chinese publication CN106821938B was used as a reference.
Regarding claims 1 and 5, Huang et al. teach method for preparing human mesenchymal stem cell freeze-dried powder (para. [0010]). Huang et al. teach the main source of autologous mesenchymal stem cells are adipose/skin stem cells (para. [0005]-[0006]).
Regarding claims 7 and 8, Huang et al. teach a method for preparing human mesenchymal stem cell freeze-dried powder including the following steps: 1) Collection: Collect high-quality human mesenchymal stem cells with passage numbers between 2 and 8; 2) Culture of mesenchymal stem cells: human mesenchymal stem cells were expanded and passaged using serum-free culture medium; 3) Cryopreservation of mesenchymal stem cells: Human mesenchymal stem cells passaged in cell cryopreservation solution were frozen to -80 degrees Celsius; 4) Preparation of freeze-dried powder: The human mesenchymal stem cells processed in step 3) are prepared into freeze-dried powder; 5) Add resurrection solution: add resurrection solution to the freeze-dried powder prepared in step 4); preferably, the cell cryopreservation solution in step 3) contains the following active ingredients: trehalose, dextran, poloxamer (P188) (a type of polyethylene glycol), glycerol, water for injection, serum-free basal culture medium, inter alia (para. [0010]-[0017]). The active ingredients of the cryopreservation solution read as a lyophilization mixture comprising various combinations of ingredients (claim 7) as the cryopreserved cells are subjected to freeze-drying (lyophilization). Trehalose is a well-known lyoprotectant, therefore, reads as lyoprotectant (claim 8).
Regarding claims 10 and 13, Huang et al. teach the lyoprotectant comprise a mixture of trehalose and dextran.
Regarding claims 20-22, Huang et al. teach, after 3 months, freeze-dried tubes of MSCs, the cells were found to be intact under a microscope and the cell viability rate was 65-70% (para [0089]). Viability rate of 70% reads as between about 15% to 97% (claim 20), about 25% to 90% (claim 21), and viability has decreased no more than about 30% (claim 22).
Regarding claim 23, the limitation “form a pharmaceutically acceptable cake after lyophilization” is not considered limiting because it recites an intended result or potential property and does not further limit the lyophilized powder.
Regarding claim 24 and 26-27, these claims all recite intended results as well as inherent properties of lyophilized stem cell powder. However, if these limitations were considered limiting the lyophilized stem cell powder, Huang et al. teach the prepared freeze-dried powder has no defects in appearance, good stability (safe and easy transportation and distribution of samples/ stable after transport), long shelf life (long-term preservation), and is not easily contaminated (para. [0087]).
Regarding claim 25, the instant specification defines “room temperature” as -25°C to up to 45°C or a temperature prevailing in a work area (instant specification, p. 15). Huang et al. teach the lyophilized powder can be stored at 4°C, which falls in the range of -25°C to up to 45°C.
Thus, the reference anticipates the subject matter of claims 1, 5, 7-8, 10, 13, and 20-27.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5, 7-10, 13, 15-18, 20-27 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (CN106821938B, published 24 March 2020) as applied to claims 1, 5, 7-8, 10, 13, and 20-27 above, and further in view of Crowe et al. (US2002/0076445, published 20 June 2002).
Huang et al. anticipate the subject matter of claims 1, 5, 7-8, 10, 13, 20-21, and 23-27, and thus, also render them obvious.
Regarding claim 9, Huang et al. do not teach wherein the ingredients in the lyophilization mixture comprise human serum albumin.
Crowe et al. teach dehydrated compositions including freeze-dried (lyophilized) eukaryotic cells (Abstract). Crowe et al. teach when eukaryotic cells are rehydrated they are immediately restored to viability (para. [0004]). Crowe et al. teach cells imbedded within a freeze-drying matrix composed of trehalose, albumin, and salts (para. [0056] and Fig. 19A). Crowe et al. teach if albumin is used, it should be from the same species as the cells and suitable other polymers include water-soluble polymers such as dextran (para. [0080]). Crowe et al. generally discuss freeze-dried platelets, however, Crowe et al. teach in additional embodiments of the present invention, it has been discovered that the general findings with respect to platelets are broadly applicable to cells, particularly eukaryotic cells (para. [0096]) to include mesenchymal stem cells (para. [0097]). Crowe et al. teach cells were resuspended in a drying buffer prior to freeze-drying, wherein the buffer comprises trehalose, human serum albumin, inter alia (para. [0135]).
Therefore, it would have been obvious to one or ordinary skill in the art to include the human serum albumin of Crowe et al. with the lyophilization mixture of Huang et al. with a reasonable expectation of success because Crowe et al. teach other polymers, such as dextran, can also be utilized as suitable bulking agents (Crowe et al., para. [0080]) and the composition taught by Huang et al. comprise dextran (Huang et al., para. [0010]-[0017]). One would be motivated to include the human serum albumin of Crowe et al. with the lyophilization mixture of Huang et al. because Crowe et al. teach a drying buffer comprising trehalose should also comprise a bulking agent, such as albumin of the same species as the cells, which assists in spatially separating the cells as well as stabilizing the membranes on the exterior of the cells (para. [0080]). Additionally, one may be motivated to include both dextran and human serum albumin as both can act as bulking agents, however, utilizing dextran as well would provide a cost savings as human serum albumin is more expensive.
Regarding claims 15-18, Huang et al. in view of Crowe et al. teach a lyophilization mixture comprising human serum albumin, trehalose, glycerol, dextran, and PEG.
Regarding claim 23, Crowe et al. teach mesenchymal stem cells were prepared for freeze-drying in a growth medium comprising trehalose, freeze-dried, and the freeze-dried cake was homogeneous and robust with no indications of collapse (para. [0165]).
Regarding claim 25, Crowe et al. teach, in example 7, the culture, freeze-drying, and rehydration of mesenchymal stem cells, wherein, following freeze-drying, the cells were slowly ramped to room temperature over a 12-hour period under vacuum (para. [0157]). This reads as the lyophilized powder was stored at room temperature.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 1, 5, 7-10, 13, 15-27 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (CN106821938B, published 24 March 2020) in view of Crowe et al. (US2002/0076445, published 20 June 2002) as applied to claims 1, 5, 7-10, 13, 15-18, 20-27 above, and further in view of Solivio et al. (Scientific Reports, published 12 April 2016) and Amin et al. (Journal of Pharmaceutical Sciences, published September 2004).
Regarding claim 19, Huang et al. in view of Crowe et al. are silent to utilizing PEG 400.
However, Solivio et al. teach lyoprotectant matrix technology for non-cryogenic storage of archival human sera, wherein, the matrix mainly comprises trehalose and dextran along with various other low concentration excipients targeting different mechanisms of damage (Abstract).
Solivio et al. teach one of these low-concentration excipients is polyethylene glycol (PEG), which is a water-soluble, biocompatible polymer shown to stabilize serum albumin (p. 7, Polyethylene glycol (PEG)). Solivio et al. teach PEG at different molecular weights were tested in desiccation experiments, specifically PEG 400-20,000 (p. 7, Polyethylene glycol (PEG)). Solivio et al. teach PEG is recognized as one of the most effective cryoprotectants, and is shown to induce stability at concentrations of 1% or less (p. 7, Polyethylene glycol (PEG)). Solivio et al. teach the lyoprotectant cocktail mainly comprised dextran and trehalose along with other low concentration excipients such as glycerol and PEG (p. 10, Lyoprotectant cocktail design).
Amin et al. teach lyophilization of cosolvent systems may be a beneficial way of enhancing both physical and chemical stability of a drug product and PEG 400 was selected because it is widely used and can be easily frozen (Abstract). Amin et al. teach the addition of PEG 400 to commonly used bulking agents, such as mannitol, sucrose, or polyvinylpyrrolidone, caused a significant change in the thermal properties of the bulking agents as observed by modulated differential scanning calorimetry (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art to choose PEG 400 in the lyoprotectant mixture of Huang et al. in view of Crowe et al. with a reasonable expectation of success because Amin et al. teach PEG 400 is widely used and can be easily frozen (Amin et al., Abstract). One would have been motivated to choose PEG 400 in the lyophilization mixture of Huang et al. in view of Crowe et al. because Solivio et al. teach PEG is shown to stabilize serum albumin (Solivio et al., p. 7, Polyethylene glycol (PEG)) and the mixture of Huang et al. in view of Crowe et al. comprises serum albumin. Additionally, Solivio et al. teach PEG at different molecular weights were tested in desiccation experiments, specifically PEG 400-20,000 (Solivio et al., p. 7, Polyethylene glycol (PEG)).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Relevant prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Zhang et al. (Stem Cell Research & Therapy (2020), published 31 October 2020)
Zhang et al. teach adipose derived stem cells and the combination of trehalose and glycerol are effective and non-toxic recipe for cryopreservation and cells showed high levels of viability and proliferation following cryopreservation.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631