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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05-21-2025 has been entered.
Applicant’s amendment and arguments filed on 04-24-2025 has been entered. Claims 1, 17 have been amended. Claims 7, 9, 12-16, 18, 24, 27-30, 33 have been canceled. Claim 36 has been added. Claims 1-6, 8, 10-11, 17, 19-23, 25-26, 31-32, 34-36 are pending.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 17-23, 25-26) in the reply filed on 07-08-2024 is acknowledged. Upon further consideration, restriction requirements between invention of group I and group II are hereby withdrawn and claims 1-8, 10-11 drawn to nonelected invention of group I is hereby rejoined with the elected invention of group II.
Claims 31-32 and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07-08-2024.
Claims 1-6, 8, 10-11, 17, 19-23, 25-26, 35-36 and species of ethylene glycol and sucrose are under consideration.
Priority
This application is a 371 of PCT/US2020/013956 filed on 01/16/2020 that that claims priority from US provisional 62/793,535 filed on 01/17/2019.
New-Claim Rejections - 35 USC § 112-necessitated by amendments
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 6 and 22 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.
Claims 6 depending on claim 1 and claim 22 depending on claim 17 both recite the limitations “the cryoprotective agent is present at a concentration of IM to 10 M”. There is insufficient antecedent basis for these limitations because it is unclear the recited concentrations refer to the beginning concentration, the final concentration or does it refer to both the initial and final concentrations (e.g., setting a range from beginning to end) ? Appropriate correction and/or clarification is required.
Maintained in modified form-Claim Rejections - 35 USC § 103 -necessitated by amendments
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.
Claims 1-6, 8, 10, 17, 19-23, 25, 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Brockbank et al. (Pub. No.: US 2018/0192639 Al, Pub. Date: Jul. 12, 2018) in view of Manuchehrabadi et al (Sci. Transl. Med. 9, eaah4586 (2017), 1 March 2017, DOI: 10.1126/scitranslmed.aah458) and Ennis et al (Patent No.: US 8,790,923 B2, Date of Patent: Jul. 29, 2014).
Claim interpretation:
The specification of the claimed invention teaches that a method of preserving tissue includes loading the tissue with a solution comprising a cryoprotective agent and susceptor particles; freezing the tissue; thawing the tissue; and after freezing and thawing, further processing the tissue. Further processing may include digesting the tissue; and recovering isolated cells from the digested tissue ([0010], page 3). The method may further include digesting the tissue and recovering isolated cells from the digested tissue. For example, the tissue may be digested using collagenase ([0049], page 14). Thus, digesting the tissue and recovering isolated cells from the digested tissue can be performed by using collagenase and considered as “processing the biospecimen after the cryopreserving and the rewarming”.
The specification of the claimed invention teaches that susceptor particles are nanoparticles ([0022], page 6). Thus, susceptor particles are interpreted as nanoparticles.
The specification of the claimed invention teaches that the susceptor particles include an iron oxide core coated with mesoporous silica followed by polyethylene glycol and trimethoxysilane. Thus, particles with iron oxide core coated with mesoporous silica are interpreted as iron oxide nanoparticles having a core-shell structure where the core comprises iron oxide and the shell comprises a non-metal.
The specification of the claimed invention does not define the phrase “homogenous distribution” in a limited way. The instant disclosure only mentions the phrase “homogenous distribution” once in [0022] on page 6 without any definition. Thus, the phrase “homogenous distribution” is interpreted broadly with their plain meaning.
Regarding to claim 1 and 17, Brockbank et al teach large volume cellular material may be preserved by combining the cellular material with a cryoprotectant formulation/medium/solution containing at least one sugar and then subjecting the cellular material to a vitrification preservation protocol (Abstract). The present disclosure relates to the field of cell, tissue and organ preservation ([0003], page 1), and the term "organ" refers to any organ, such as, for example, liver 0028], page 3). For the preample of claim 1 and 17).
Brockbank et al teach the cellular material to be preserved may be brought into contact with a cryoprotectant-containing solution, and the duration that the tissue may be contacted by perfusion in such solution/medium/formulation/composition will be a function of the mass of the tissue ([0053], page 5) (For Claim 17, the claimed: “perfusing a biospecimen comprising at least a portion of a liver”,).
Brockbank et al teach that in some embodiments, at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) in combination with other cryoprotectants, is used in an amount in the methods of the present disclosure such that it results in an improved viability (post-cryopreservation) of the living cellular material/sample selected from the group consisting of organs, cells and tissues ([0046], page 4, and Fig 1). Rabbit thoracic aorta samples were vitrified in 30 mL volumes of VS55 with or without 0.6M sucrose with or without nanoparticles for comparison of convection versus nanowarming. The results are set forth in FIG. 5 (30 mL rabbit thoracic aorta results demonstrating improved outcomes with sucrose supplementation using either convection (middle bar) or nanowarming (far right bar)) ([0105], page 11) (For claims 1 and 17, the claimed: “loading the biospecimen with a solution comprising a cryoprotective agent and susceptor particles; cryopreserving the biospecimen”).
Brockbank et al teach vitrification method: Tissues were gradually infiltrated with precooled dilute vitrification solutions (4° C.) (cryoprotective agent) which are added in five sequential 15-min steps of increasing concentration on ice. The last cryoprotectant concentration with mNPs (magnetic nanoparticles) was added in a final sixth addition step in either precooled -10° C. or 4° C.( [0091] - [0092], page 10). Additionally, Brockbank et al teach that the final cryoprotectant concentration may be reached in a stepwise cooling process in which the sample to be preserved (such as a cellular material or tissue) may be immersed in a first solution containing a first cryoprotectant concentration, then the tissue may be immersed in a second solution containing a second cryoprotectant concentration (which is higher than the first cryoprotectant concentration), and this process may be repeated with a third, fourth, fifth, sixth, seventh, etc., solution until the desired concentration is achieved. The cryoprotectant solution may contain any combination of cryoprotectants ([0071], page 8). (For claims 1 the claimed: “with a cryoprotective agent at a first concentration and increasing the first concentration of cryoprotective agent during loading and finally adding susceptor particles and the cryoprotective agent at the increased concentration to load the tissue”, and For claims 17 the claimed: “loading the specimen with a cryoprotective agent at a first concentration; loading the biospecimen with a solution comprising the cryoprotective agent at a second concentration greater than the first concentration and susceptor particles”)
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Brockbank et al teach that the formulation/solution/medium may be contacted with the sample to be preserved for any desired duration, such as until a desired dosage (such as an effective dosage) of the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) is present on/in the cells or tissues to afford an improved viability (post-cryopreservation) ([0050], page 5). Thus, a person of ordinary skill would contact the tissue sample until homogenous distribution of the solution is present on/in the cells or tissues (For claims 1 and 17, the claimed: “a homogenous distribution of a solution”).
Brockbank et al teach warming was performed by either convection warming or nanowarming ([0094], page 10). In some embodiments, low radio-frequencies and inductive heating may be used to heat when combined with distributed biocompatible magnetic nanoparticles (mNPs) ([0076], page 8) (For the claimed: “magnetically inducing heating of the homogenous distribution of susceptor particles to rewarm the tissue” in claim 1 and “rewarming the biospecimen by magnetically induced heating of the susceptor particles” in claim 17 ).
Brockbank et al does not specifically disclose iron oxide nanoparticles. Manuchehrabadi et al cure the deficiency.
Manuchehrabadi et al teaches improved tissue cryopreservation using inductive heating of magnetic nanoparticles (title) and present a scalable nanowarming technology for 1- to 80-ml samples using radiofrequency-excited mesoporous silica–coated iron oxide nanoparticles in VS55 (Abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Brockbank et al by using mesoporous silica–coated iron oxide nanoparticles for nanowarming as taught by Manuchehrabadi et al as instantly claimed with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Manuchehrabadi et al teaches explicit advantage of improved tissue cryopreservation using inductive heating of magnetic nanoparticles (title) and improved viability compared to slow-warmed (crystallized) samples (abstract). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Manuchehrabadi et al provides proof of principle for nanowarming using silica–coated iron oxide nanoparticles in VS55 with working examples and detailed instruction.
Brockbank et al does not specifically disclose processing the biospecimen after the cryopreserving and the rewarming. However, Ennis et al cure the deficiency.
Ennis et al teach digesting the tissue; and recovering isolated cells from the digested tissue from frozen samples: Viable progenitor cells are extracted from frozen umbilical cord tissue (Abstract). The vessels bearing the proximal perivascular tissue, or sections thereof, are then incubated at about 37° C. in an extraction medium such as phosphate buffered saline (PBS) containing an enzyme suitable for digesting the collagen matrix of the perivascular tissue in which the desired cells reside. For this purpose, digestion with a collagenase is suitable, (column 12, lines 32-40). After about 24 hours in the 0.5 mg/mL collagenase extraction medium, the vessels are removed, leaving a perivascular tissue extract that contains human progenitor cells. These cells are expanded under conditions standard for expansion of progenitor cells (column 13, lines 1-7). Given that Brockbank et al teaches vitrification preservation protocol for liver tissue that inherently contains hepatocytes and perivascular tissue, and digestion of tissue with a collagenase is routinely performed in the art as described by Ennis et al, a person of ordinary skill in the art would be able to process the liver by digesting and recovering isolated hepatocyte (For the claimed: “processing the biospecimen after the cryopreserving and the rewarming” in Claims 1 and 17, and “comprising digesting the rewarmed biospecimen and recovering isolated hepatocytes from the digested biospecimen” in claim 17).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Brockbank et al of cryopreserving and the rewarming organ or tissue by processing or digesting the tissue and recovering isolated cells from the digested tissue as taught by Ennis et al with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Ennis et al provides explicit advantage of cryopreservation of organ and obtaining viable cell after cryopreservation and preserving the viability of cells (column 3, lines 35-40). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Ennis et al was successful in preserving cells and obtaining viable cells after cryopreservation, and Ennis et al provides detailed guidance and working examples for digesting the tissue and recovering isolated cells from the digested tissue.
Regarding to claims 2, Brockbank et al teach the term "organ" refers to any organ, such as, for example, liver, lung ([0028], page 3).
Regarding to claim 3 and 19, Brockbank et al teach cryoprotectant for a living material/ sample selected from the group consisting of organs, cells and tissues, such as mammalian organs ([0060], page 6). Brockbank teaches the term "organ" refers to any organ, such as, for example, liver, lung ([0028], page 3).
Regarding to claim 4 and 20, Brockbank et al teach the cellular material to be preserved may be brought into contact with a cryoprotectant-containing solution, and the duration that the tissue may be contacted by immersion and/or perfusion in such solution/medium/formulation/composition will be a function of the mass of the tissue ([0053], page 5) (Note: Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue (Wikipedia definition)).
Regarding to claim 5 and 21, Brockbank et al teach cryoprotectant is selected from the group consisting of ethylene glycol and sucrose ([0080], page 9, right column).
Regarding to claim 6 and 22, Brockbank et al teach that if desired, the cryoprotectant formulation may contain the further cryoprotectant at a concentration of from 0.1 to 13.0 M ([0080], page 9, right column; [0052], page 5).
Regarding to claim 8, 23, Brockbank et al teach in some embodiments, low radiofrequencies and inductive heating may be used to heat when combined with distributed biocompatible magnetic nanoparticles (mNPs) ([0076], page 8). Additionally, Manuchehrabadi et al teaches silica–coated iron oxide nanoparticles (Abstract). Mesoporous silica– coated iron oxide nanoparticles (msIONPs) are relatively monodispersed with one to two iron oxide cores per particle (Page 2, right column, 2nd para.)
Regarding to claims 10 and 25, Ennis et al teach digesting the tissue; and recovering isolated cells from the digested tissue from frozen samples: Viable progenitor cells are extracted from frozen umbilical cord tissue (Abstract). The vessels bearing the proximal perivascular tissue, or sections thereof, are then incubated at about 37° C in an extraction medium such as phosphate buffered saline (PBS) containing an enzyme suitable for digesting the collagen matrix of the perivascular tissue in which the desired cells reside. For this purpose, digestion with a collagenase is suitable, (column 12, lines 32-40). After about 24 hours in the 0.5 mg/mL collagenase extraction mediumthe vessels are removed, leaving a perivascular tissue extract that contains human progenitor cells. These cells are expanded under conditions standard for expansion of progenitor cells (column 13, lines 1-7).
Regarding to claim 35, Brockbank et al teach wherein the medium does not contain DMSO, formamide and/or propylene glycol (see claim 12, page 13). Brockbank also teaches the methods of the present disclosure may use and/or achieve a medium/solution and/or cellular material that is substantially free of cryoprotectant, such as a cellular material that is substantially free of DMSO ([0039], page 4).
Regarding to claim 36, Brockbank et al teach vitrification method: Precooled dilute vitrification solutions (4° C.) (cryoprotective agent) are added in five sequential 15-min steps of increasing concentration on ice. The last cryoprotectant concentration with mNPs (magnetic nanoparticles) was added in a final sixth addition step in either precooled -10° C. or 4° C.( [0091] - [0092], page 10).
Claims 11 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Brockbank et al. (Pub. No.: US 2018/0192639 Al, Pub. Date: Jul. 12, 2018) in view of Manuchehrabadi et al (Sci. Transl. Med. 9, eaah4586 (2017), 1 March 2017, DOI: 10.1126/scitranslmed.aah458) and Ennis et al (Patent No.: US 8,790,923 B2, Date of Patent: Jul. 29, 2014) as applied to claims 1-6, 8, 10, 17, 19-23, 25, 35-36 above , and further in view of Straussman et al (Pub. No.: US 2020/0224171 Al, Provisional application No. 62/481,738, filed on Apr. 5, 2017).
Brockbank et al and Ennis et al do not specifically teach the processing the biospecimen comprises slicing the biospecimen and/or isolating sections of the biospecimen. However, Straussman et al cures the deficiency.
Regarding to claim 11 and 26, Straussman et al teaches that according to specific embodiments, the tissue is cryopreserved following tissue retrieval and prior to cutting. According to specific embodiments, the tissue is thawed prior to cutting ([0096]-[0097], page 5). Straussman et al also states that tissue slice maintains the structure and presents high viability following 5 days of culture, this system allows modeling of chronic as well as acute toxicity studies, including the metabolic activity of the tissue ([0179], page 7).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of the above references by cutting the tissue after being cryopreserved and thawed as taught by Straussman et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Straussman et al provide explicit advantage of the tissue slice maintains the structure and presents high viability following 5 days of culture ([0179], page 7). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Straussman et al was successful in maintaining high viability of cells after being cryopreserved and thawed, and Straussman et al also provides detailed instruction for Ex-vivo culture systems using cryopreserved tissue.
Response to Arguments
Applicant's arguments filed 04-24-2025 have been fully considered but they are not persuasive. Response to Applicants' arguments with respect to newly added limitation can be found as described above.
Applicant disagrees that such disclosure does not make obvious the claimed “a homogenous distribution of a solution comprising a cryoprotective agent and susceptor particles”, and the claims are directed to achieving the distribution by first loading the cryoprotective agent at a first concentration and then increasing the concentration of the cryoprotective agent and including the susceptor particles with the increased concentration of the CPA. That is, merely contacting the tissue does not achieve what is claimed and moreover, the claimed method includes steps not made obvious by the disclosure of Brockbank (or other cited prior art). In contrast, it is not obvious to reach homogenous distribution of the solution comprising the cryoprotective agent and the susceptor particles in the method claimed by first loading cryoprotective agent and increasing the concentration of the cryoprotective agent when finally adding the susceptor particles. Brockbank does not make obvious, alone or in combination, the susceptor particles are added at the increased CPA concentration or final step and instead such overall method claimed is only made obvious in view of the Applicant's own disclosure (see para. [0055]) (Remarks, Page 7-9)
Response to Arguments
It is noted that, as described above, Brockbank et al teach vitrification method: Tissues were gradually infiltrated with precooled dilute vitrification solutions (4° C.) (cryoprotective agent) which are added in five sequential 15-min steps of increasing concentration on ice. The last cryoprotectant concentration with mNPs (magnetic nanoparticles) was added in a final sixth addition step in either precooled -10° C. or 4° C.( [0091] - [0092], page 10). Additionally, the specification of the claimed invention does not define the phrase “homogenous distribution” in a limited way. The instant disclosure only mentions the phrase “homogenous distribution” once in [0022] on page 6 without any definition. Brockbank et al teach that the formulation/solution/medium may be contacted with the sample to be preserved for any desired duration, such as until a desired dosage (such as an effective dosage) of the at least one sugar, such as a disaccharide (e.g., trehalose and/or sucrose) is present on/in the cells or tissues to afford an improved viability (post-cryopreservation) ([0050], page 5). Additionally, Brockbank et al teach that the final cryoprotectant concentration may be reached in a stepwise cooling process in which the sample to be preserved (such as a cellular material or tissue) may be immersed in a first solution containing a first cryoprotectant concentration, then the tissue may be immersed in a second solution containing a second cryoprotectant concentration (which is higher than the first cryoprotectant concentration), and this process may be repeated with a third, fourth, fifth, sixth, seventh, etc., solution until the desired concentration is achieved. The cryoprotectant solution may contain any combination of cryoprotectants ([0071], page 8). Thus, a person of ordinary skill would contact the tissue sample until homogenous distribution of the solution is present on/in the cells or tissues.
Applicant has not provided evidence for contacting the tissue does not achieve what is claimed. As per MPEP 716.01 (c) (II), Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632