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 .
Election/Restrictions
Claims 21-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to the nonelected group I, a method of using umbilical cord derived mesenchymal stem cells as a treatment, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/8/2026
Applicant's election with traverse of mesenchymal stem cells (group II) in the reply filed on 6/8/2026 is acknowledged. The traversal is on the ground(s) that groups I (method of using mesenchymal cells as treatment), and group II (the mesenchymal cells themselves) do not lack unity of invention. This is not found persuasive because lack of unity is the wrong restriction standard for this application. The application is not a 371 filing. The instant application is a “bypass continuation” application. This categorization is supported by the application Electronic Fee Payment form which explicitly states that the application type is 111(a). Therefore, restriction is governed under MPEP 806.05(h). One way distinctness is the standard. While applicant has argued why the process cannot be performed with a materially different product, applicant has not addressed why the product (hUC-MSCs) cannot be used in the materially different process of facilitating iPSC differentiation in-vitro by acting as a feeder layer for adherent cell culture. This was the original rationale for restriction. Additionally, the applicant’s argument of no search burden is not persuasive. The originally cited restriction rationale (product can perform a different process) has not been addressed. Therefore, the elected invention and the non-elected invention are still distinct, and require the use of different search strategies using alternative invention categorizations and different keyword combinations.
The requirement is still deemed proper and is therefore made FINAL.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 28-35 are rejected under 35 U.S.C. 101 because the claimed invention(s) are directed to a product of nature without significantly more.
Claims 28-31 recite, “isolated human umbilical cord-derived mesenchymal stem cells”. As claimed, the cells are a naturally occurring product that can be found in mammalian tissues (eg; umbilical cord tissue) and therefore recite a judicial exception; a product of nature. This judicial exception does not amount to significantly more because the claims do not recite any additional elements that provide/indicate structural and/or functional characteristics of the claimed cells that are markedly different from their natural counterpart(s). Importantly, the recited combination of phenotypic markers possessed by the claimed cell(s) (positive expression of CD73, CD90 and CD105 at a level of at least 95% and negative expression of CD34, CD45, CD1lb, CD19 and HLA-DR at a level of less than 2%) is a combination that 1) occurs naturally, and, 2) is the phenotypic pattern used by the field to identify/define naturally occurring mesenchymal stem cells. (See Dominici M et al 2006). With regard to the current scenario, isolation and/purification these naturally occurring cells does not impart sufficient structure or functional characteristics that would render them patent eligible. Therefore, the claimed cells retain the same identity and biological properties as their naturally occurring counterparts. Accordingly, the cells as claimed do not amount to significantly more than the judicial exception and thus are not patent eligible.
Claims 32-33 recite, “cryopreservation preparation of…the isolated human umbilical cord-derived mesenchymal stem cells according to claim 28 and a cell cryoprotectant;”. The claimed preparation is directed toward a judicial exception (aka the naturally occurring mesenchymal stem cells. See above for cell’s 101 rejection rationale). The addition of a conventional component (aka cryoprotectant which also includes products of nature such as human albumin) performing its ordinary and expected function (preserving cell viability during freezing) does not impart markedly different characteristics to the claimed cells. The cryoprotectant does not change the nature of the cells. Absent any indication the claimed cryopreservation preparation possesses structural and/or functional characteristics that are markedly different from those of the naturally occurring mesenchymal stem cells, the claimed preparation does not recite additional elements sufficient to render the claim patent eligible. Therefore, the claims are directed towards a judicial exception and do not recite additional elements that amount to significantly more than the judicial exception. Therefore, the claims are not patent eligible.
Claims 34-35 recite, “The cryopreservation preparation of human umbilical cord-derived mesenchymal stem cells according to claim 32 for use in the prevention or treatment of a disorder…”. Importantly, the claimed cryopreservation preparation is still directed toward a judicial exception (naturally occurring mesenchymal stem cells), the additional component(s) (aka cryoprotectant) still do not impart structural and/or functional characteristics that make the cells markedly different from their naturally occurring counterpart, and the additional limitation of “for use in preventing or treating...” is simply an intended use of the claimed preparation. This intended use of the preparation does not impose any additional structure or otherwise alter the characteristics of the claimed preparation. Therefore, the claimed preparation remains directed to a judicial exception (aka a product of nature) and the intended-use limitation does not amount to significantly more because it does not render the preparation markedly different than its natural counterpart. Therefore, the claims are not patent eligible.
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.
Claims 28-29,31-37,39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gong W et al 2012.
Gong W et al 2012 discloses human umbilical-cord tissue block isolated mesenchymal stem cells (hUC-MSCs) wherein ≥ 95% are positive for CD105, CD73, CD90. They also show the cells are negative (≤2%) for CD45, CD34, CD31, CD11b, CD19, HLA-DR (claim 28). They also disclose a cryopreservation solution wherein 1X10^7 cells/ml (hUC-MSCs) are resuspended in the cryoprotectant DMSO, aliquoted, and then frozen by successively lowering the temperature (claims 32-33,36-37,39). Specifically, “… properties and safety of UC-MSCs were then characterized …The biological properties, such as plastic adherence, morphology, specific surface antigen (CD105, CD73, CD90, positive ≥ 95%; CD45, CD34, CD31, CD11b, CD19, HLA-DR, negative ≤2%)…were retained.” (abstract). Importantly, “MSCs were isolated from umbilical cord…umbilical cord was minced and digested.” (paragraph “Isolation and Primary Expansion” in materials and method section). Additionally, “cells were resuspended in a cryoprotectant solution composed of 90% FBS and 10% dimethyl sulfoxide (DMSO) (Edwards Lifesciences) and stored at −80°C overnight, then transferred to the vapor phase of a liquid nitrogen tank.” (paragraph “cryopreservation” in materials and methods section).
Additionally, claims 34-35 list an intended use (claim 34) and the nature of the use condition (claim 35). These claims do not add any meaningful structure/limitations to the claimed composition of claim 32, and therefore hold no patentable weight. Thus, the cryopreservation preparations of claim 34-35 are identical to the preparation of claim 32 and are therefore anticipated by Gong W et al 2012.
Furthermore, claims 29,31 are directed to the procedural steps of claim 28. These procedural/process steps, which are intended to define how the product of claim 28 (aka the hUC-MSCs) are prepared, add no structure to the cells (MPEP 2113). Thus, claims 29,31 carry no patentable weight and their recited hUC-MSCs are also anticipated by Gong W et al 2012.
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 30,38,40 are rejected under 35 U.S.C. 103 as being unpatentable over Gong W et al 2012 as applied to claim 28 above, and further in view of Fujita Y et al 2021, Woods E et al 2016, Mazur P et al 2007, and Hansen R et al 2011.
Gong W et al 2012 discloses a method for preparing a preparation of cryopreserved hUC-MSCs which are defined by the aforementioned phenotypic markers. They also disclose using a cryoprotectant (DMSO) and lowering the temperature of the solution to cryopreserve cells.
Gong W et al 2012 does not disclose the stem cell solution of claim 28 be at a concentration of 8*10^6 cells/ml, or the use of multiple cryoprotective agents (CPAs) in specific volume rations as in clam 38, or the specific method steps outlined in claim 40, which detail the rate of cooling and the steps in cooling.
Fujita Y et al 2021 discloses a DMSO-based cryopreservation solution wherein the addition of dextran-40 improved viability of vitrified human mesenchymal stem cells. Specifically, “LR-3T-5D was superior to LR-3T as a replacement solution in terms of viability and annexin V positivity.” (abstract)
Hansen R et al 2011 disclose a DMSO-based cryopreservation solution including electrolytes (Normosol-R) and Human Albumin. (see: Materials for Cryopreservation of Hematopoietic Cells, page 1).
Woods E et al 2016 discloses that controlled-rate, step-wise cooling is the gold standard when preparing cell therapies for liquid nitrogen immersion/storage. They also provide rationales for why optimization and validation of the cryopreservation process is essential for developing accurate shelf-life estimates. Specifically, “As discussed earlier, the use of cryogenic temperatures (below −150°C) is often applied for cell therapies…These cell-based products are usually frozen down using a controlled-rate step-wise process using both manual and automated systems.” (paragraph 2, “Factors pertaining to systems and devices” section). Additionally, “For these reasons, when developing a shelf-life estimate for cryopreserved cells, if cryopreservation processing methods are optimized and have been validated, and assuming a storage temperature of <130°C, it is more appropriate to base the shelf life on how many transient events will occur (either due to LN2 storage tank level or sample removal) than on time itself.” (paragraph 9 under “Storage injury” section).
Mazur P et al 2007 discloses that interrupted cooling is highly beneficial for cryopreservation survival rates. Specifically, “Finally, when the oocytes were held 30 or 40 min, relatively few flashed during either cooling or warming… We conclude that 30 min at −25°C removes nearly all intracellular freezable water…” (abstract).
It would be obvious to a person of ordinary skill in the art, before the effective filing date, to use Dextran-40 as an additional CPA, as disclosed in Fujita Y et al 2021, in the DMSO-based, human albumin and electrolyte cryoprotectant solution of Hansen R et al 2011. The addition of dextran-40 to cryopreservation solutions reduces the concentration of DMSO needed for effective cryoprotection. Considering DMSO’s cellular toxicity, this is a major advantage.
Additionally, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to employ the controlled, stepwise cooling methodology disclosed in Woods E et al 2016 when using the aforementioned solution according to the method of resuspension and cooling as disclosed in Gong W et al 2012. Slow, controlled, step-wise cooling supports the steady growth of extracellular ice, which allows for the osmotic efflux of water from the cell while driving up the intracellular viscosity toward forming glass, as supported by Woods et al 2016. This prevents the formation of intracellular ice crystals which often damage or kill cells during freeze/thaws.
It would also be obvious to a person of ordinary skill in the art, before the effective filing date, to use an interrupted-cooling step, as disclosed in Mazur P et al 2007, in the aforementioned cooling/freezing protocol. The interrupted cooling step removes nearly all the intracellular freezable water, and therefore prevents the formation of ice crystals in cells during freezing or warming. Importantly, the specific ratios of cryoprotective agents (CPAs) disclosed in claim 38, and the temperatures points and cooling rates disclosed in claim 40 are all routine optimizable parameters. Support for this conclusion is grounded in the fact that whether a prescribed cooling rate is too “slow” or too “fast”, and whether a particular CPA and its concentration are effective, is a function of cell membrane permeability and the probability that any water remaining trapped within the cell at a given subzero temperature will nucleate and turn to ice. Because the difference in membrane permeability and probability of ice crystal formation results in different optimal cooling rates for different cells, quantitative understanding of water transport across the cell membrane during cryopreservation is critical for the success of a respective protocol, as supported by Woods et al 2016. Additionally, the types and concentrations of CPAs need to be fine-tuned to balance cellular osmotic stress and chemical toxicity, which are both cell line dependent, as supported by Zheng S et al 2024.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Adam M Smith whose telephone number is (571)272-7517. The examiner can normally be reached Monday- Friday 10:30AM-5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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