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 .
Amendments
In the reply filed 5/27/2026, Applicant has amended Claims 1-6, and added new claims, Claims 7-17.
Claims 1-17 are under consideration.
Withdrawn Objections to the Specification
The prior objection to the disclosure has been withdrawn due to Applicant’s amendment to the specification.
Withdrawn Claim Objections
The prior objections to Claims 1-6 have been withdrawn due to Applicant’s amendments to the claims.
Withdrawn 35 USC § 112(b)
The prior rejection of Claims 1-6 under 35 U.S.C. § 112(b) pre-AIA 2nd paragraph as being indefinite is withdrawn in light of Applicant’s amendments of Claim 1 to describe a the reduced proportion of epithelial cells.
New Claim Rejections - 35 USC § 112(d)
as necessitated by amendment
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Specifically, claim 3 draws to a method of producing amnion-derived MSC where the buffer of claim 1, step (1) is an aqueous solution, gel or sol, which does NOT narrow the scope of claim 1 where the buffer is an aqueous solution. Essentially, due to the applicant’s own claim language, the gel or sol embodiments of claim 3 are excluded from the scope of claim 1. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-6, 9-10, 13 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Yamahara et al., (US2016/0228474, see IDS filed 9/25/2023)
In regard to claims 1 and 13, Yamahara teaches methods for producing a population of amnion-derived MSCs comprising the following 9 steps (see p. 5, col 1, [0085-0094]:
Step 1. Aseptically obtaining human fetal appendages (e.g., placenta, umbilical cord, and fetal membrane) from a Caesarean section.
Step 2. Removing the amnion from the fetal appendages.
Step 3. Transferring and washing the amnion with a isotonic solution in order to remove blood and the like.
Step 4. Cutting the amnion into several smaller pieces, and preserving the amnion in a “medium” at 2°C to 8°C for 24 to 48 hours, which would have been an obvious step to include if the Caesarean did not occur at a convenient time or place for tissue processing in a cell culture facility. In regard to the “medium” of Yamahara as being or consisting of a “buffer” as per claims 1 and 13, Applicant’s specification states that examples of buffers include “a culture solution, …a blood-derived component, and a mixture of them.” [0021]. Thus the generic preservation medium, which Applicant categorizes as a culture media (see Remarks below), make obvious said generic “buffer”.
Step 5. The amnion is immersed in an enzyme solution comprising collagenase and thermolysin and/or dispase, and then stirred and shaken at 37°C at 60 rpm for 90 min using a thermostatic shaker.
Step 6. The MSCs are suspended in the enzyme solution, while the epithelial cells remain as a monolayer.
Step 7. Filter the enzyme solution only allowing the MSCs to pass through a mesh, while the epithelial cell layers remain. Thus, Yamahara implies the removing of undigested material that did not pass through the mesh, such that the enzyme digested fraction has a reduce proportion of epithelial cells.
Steps 8-9. Centrifuging the MSCs and resuspending in media, followed by seeding for culture.
However, Yamahara is silent to a preferred embodiment of a method for producing amnion MSCs comprising all of the taught steps.
Nevertheless, it would have been obvious to one having ordinary skill in the art at the time the invention was filed to practice said method to produce a amnion MSCs because each of the individual steps of the instant claims are independently presented by Yamahara as embodiments and are taught that they can be combined in various embodiments; therefore a combination of all the steps into a single embodiment would be apparent to an artisan skilled in primary cell culture in light of the Supreme Court’s KSR decision (see MPEP 2143 Exemplary Rationale (A)). Regarding the rationale for combining prior art elements according to known methods to yield predictable results, all of the claimed elements and steps were known in the prior art and one skilled in the art could have combined the element as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art at the time of filing of the invention. Each of the elements (storing the amnion in buffer, treating amnion in enzymes, filtering and culturing the enriched amnion MSCs) are taught by Yamahara and further they are taught in various combinations and are shown to be used in a method for producing amnion MSCs. It would have been therefore predictably obvious to use a combination of these steps and elements in said method.
In regard to claim 2, as stated supra, Yamahara teaches the amnion is “immersed in a solution” containing the enzymes, which implies the tissue was removed from the buffer before being placed in the solution. Furthermore, this would have been an obvious step so as to minimize contamination of the enzyme solution by the media.
In regard to claim 3, although Yamahara does not define the phase of the buffer, all of the other media used by Yamahara are aqueous solutions, which would have been obvious for the hypothermic storage buffer.
In regard to claim 4, as stated supra, Yamahara teaches the enzymes include collagenase and dispase.
In regard to claim 5, as stated supra, Yamahara teaches the amnion is first cut into several smaller pieces before being stored in the buffer. Note that Applicant’s does not have a special definition for “shredded” and only indicates that it may encompass being “cut into small pieces”, wherein the size of “small” is not defined. Thus, the cutting step of Yamahara appears to reasonably suggest being “shredded”.
In regard to claim 6, as stated supra, Yamahara teaches the buffer is between 2°C to 8°C.
In regard to claim 9, as stated supra, Yamahara teaches the amnion is stored in the buffer is less than 5 days.
In regard to claim 10, Yamahara teaches embodiments where the enzyme digestion is varied, which produces cell populations with less than 10% CD324+ positive epithelial cells (Table 5, condition #53, but see also Fig. 3.1, Fig.7.43, Fig. 11.81-84). Although Yamahara measure CD324 (i.e., E-cadherin), and not CD326 (i.e., EpCAM), Yamahara equates these two epithelial markers as substantially interchangeable, and also makes obvious producing cell populations with under 10% epithelial cells [0034, 0083, 0010], because it is the amnionic stem cells that have the capacity to differentiate into other cell types and are most desirable for therapeutic purposes [0003-0006]. Furthermore, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" (i.e., less than 20% encompasses less than 10%) a prima facie case of obviousness exists. 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). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05.
In regard to claims 15 and 16, although Yahamahara does not measure the total number of epithelial cells after the hypothermic storage step, it is well known that during hypothermic storage, increased membrane leakage combined with cold-induced dysfunction of membrane pumps, result in perturbation of intracellular ionic balance that can initiate apoptotic and necrotic pathways. Thus, it would have been expected that the hypothermic storage step would have reduced the number of amnionic epithelial cells. Furthermore, it is noted that the "wherein the total number of epithelial cells is reduced during the storage step” clause does not recite any additional active method steps, but simply states a characterization or conclusion of the results of process step positively recited (e.g. hypothermic storage). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.”
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 5/27/2026 are acknowledged.
First, Applicant argues that Yamahara teaches the storing step of claim 1, step (1) is in a medium, which one of ordinary skill would have understood in the context of Yamahara was a “culture media”. By contrast, instant amended claims now recite the hypothermic step is in an aqueous solution that “is a buffer”, and/or the buffer is not a culture solution. Applicant argues that under the holdings of Duke Univ v. BioMarin Pharm Inc, 685 F. App’x 967,974-977 (Fed. Circ. 2017), the use of “is” in the context of the claim itself and the supporting disclosure has a narrow meaning and does not mean “comprises”.
Second, Applicant argues that the inventors have demonstrated that this hypothermic step in a buffer reduces the proportion of CD326 epithelial cells, and Examples 6 & 7 demonstrate that a Hank’s buffered saline solution (HBSS) reduces the epithelial cells to 4.4%, compared to a MEM medium with epithelial cells at 8.45%. Furthermore, Applicant argues that Tables 1 & 2 demonstrate that using HBSS over extended periods of 4 hr to 96 hr surprisingly limited the cell death of amniotic MSCs while amniotic epithelial cells died by a greater proportion.
Applicant's arguments have been fully considered but they are not persuasive.
In regard to Applicant’s first argument that under the holdings of Duke Univ v. BioMarin Pharm Inc, 685 F. App’x 967,974-977 (Fed. Circ. 2017), the use of “is” has a narrow meaning and does not mean “comprises”, as a first matter, the focus of the Federal Circuit’s decision for the interpretation of “is” was limited to administering a composition that “is” a precursor protein (of the hGAA) as excluding a mixture of the precursor and the mature hGAA protein. The decision states “That sentences structure makes clear that the “is a precursor” phrase limits the form of hGAA to a precursor form.” However, the Federal Circuit agreed with the Board decision that the “precursor” form included a genus of options and states “we agree with BioMarin that the Board constructed “precursor” to mean any precursor of recombinant hGAA”. In instant case, the Examiner agrees that phrase “is a buffer” as per amended claim 1, and wherein the buffer “is a balanced salt solution” as per new claim 7, does limit the claimed hypothermic incubation step to a buffer or balanced salt solution, but also allows a genus of many types of buffers and a genus of many types of balanced salt solutions.
In regard to the scope of the term “buffer”, Applicant’s specification states: “Examples thereof include a buffer such as phosphate-buffered saline (PBS), a balanced salt solution such as Hanks' balanced salt solution (HBSS) and Earle's balanced salt solution (EBSS), an infusion solution such as Ringer's solution, lactated Ringer's solution, and physiologic saline, a culture solution, an albumin solution, an aqueous solution comprising a blood-derived component, and a mixture of them.”
Although the hypothermic method step of instant claims is limited to a “buffer”, the genus of buffers as defined by Applicant’s broad number of examples encompasses a subgenus of culture solutions (i.e., culture media supplemented with serum and/or albumin). Note that Applicant goes on to define “culture solution” as “used herein is not particularly limited, and can be prepared by supplementing as necessary a basal medium; i.e., any liquid medium for cell culture, with other components (e.g., albumin, a blood-derived component, and a growth factor), as appropriate.” [0023].
Thus, In response to Applicant's argument that the reference of Yamahara fails to show certain features of applicant’s invention (i.e., the buffer is not a culture media), it is noted that the features upon which applicant relies are not recited in the rejected claim(s).
In respond to Applicant’s second arguments, that the inventors have unexpected demonstrates that the hypothermic step caused proportionally more amnionic epithelial cells to die over amniotic MSCs, as a first matter, Applicant only demonstrates this effect in a single type of buffer (i.e., Hank’s buffer saline solution without Ca2+ and Mg2+), and for specific period of time, and at a specific temperature. For example, there is no selective decrease in epithelial cells at 10’C for 144 hours as demonstrated in Figs. 7.2 in HBSS vs 9.2 in MEM. Thus, the genus of buffers, the range of temperatures, and length of time claimed is not commensurate in scope with Applicant’s purported unexpected results, see Grasselli, 713 F.2d at 743, 218 USPQ at 778 (evidence of superior properties for sodium containing composition insufficient to establish the non-obviousness of broad claims for a catalyst with “an alkali metal” where it was well known in the catalyst art that different alkali metals were not interchangeable and applicant had shown unexpected results only for sodium containing materials); In re Greenfield, 571 F.2d 1185, 1189, 197 USPQ 227, 230 (CCPA 1978) (evidence of superior properties in one species insufficient to establish the nonobviousness of a subgenus containing hundreds of compounds); In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972) (one test not sufficient where there was no adequate basis for concluding the other claimed compounds would behave the same way).
Claims 7, 11, 12, 14 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Yamahara et al., (US2016/0228474, see IDS filed 9/25/2023), in view of Muraki et al. (Tissue Eng, 2006, 12:1711-1719)
Phosphate-buffered saline embodiments
A stated supra in regard to claim 1, and in regard to claim 14, Yamahara suggests a multi-step method of producing a cell population comprising amnion-derived MSC comprising (1) the step of hypothermic storage of the amnion in a “buffer” at 2°C to 8°C for 24 hours, (2) the step of treating the amnion with one or more digestive enzymes to at least partially digest the amnion tissue, (3) the step of removing the undigested amnion tissue, and (4) the step of culturing the enzyme digested amnion fraction comprising MSCs (see p. 5, col 1, [0085-0094]).
However, Yamahara is silent to the buffer being a balanced saline solution such as PBS.
In regard to claims 7, 11, 12 and 14, Muraki teaches a method for the hypothermic preservation of human MSCs at 4°C for 24 hours in the balanced salt solution of PBS, which is not a culture solution (Abstract, Fig. 1).
Accordingly, it would have been obvious to practice to one of ordinary skill at the time of filing to practice the method of Yamahara comprising the hypothermic storage step in a buffer, and choose a balanced salt solution such as PBS as taught by Murakii with a reasonable expectation of success. One of ordinary skill would have been motivated to do so as taught by Muraki because the human MSCs hypothermally stored in PBS could be delivered to distant medical facilities for tissue therapy (Abstract), and that storage in PBS for up to 24 hours could maintain high level of viability and capability of differentiation in vitro and in vivo (p. 1717, Results, last para.).
In regard to claim 17, although Yahamahara does not measure the total number of epithelial cells after the hypothermic storage step, it is well known that during hypothermic storage, increased membrane leakage combined with cold-induced dysfunction of membrane pumps, result in perturbation of intracellular ionic balance that can initiate apoptotic and necrotic pathways. Thus, it would have been expected that the hypothermic storage step would have reduced the number of amnionic epithelial cells. Furthermore, it is noted that the "wherein the total number of epithelial cells is reduced during the storage step” clause does not recite any additional active method steps, but simply states a characterization or conclusion of the results of process step positively recited (e.g. hypothermic storage). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.”
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 5/27/2026 are acknowledged and have been addressed above.
Claims 8 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Yamahara et al., (US2016/0228474, see IDS filed 9/25/2023), in view of Muraki et al. (Tissue Eng, 2006, 12:1711-1719), as applied to claims 1, 7 and 11, in further view of Ganchas-Soares et al. (WO2009/044379, filed 10/04/2007, published 4/09/2009) and Ra et al. (US 8,455,251, filed 1/10/2008, patented 6/04/2013)
Hank’s buffered saline solution embodiments
A stated supra, Yamahara in view of Muraki suggest a multi-step method of producing a cell population comprising amnion-derived MSC comprising (1) the step of hypothermic storage of the amnion in PBS at 2°C to 8°C for 24 hours, (2) the step of treating the amnion with one or more digestive enzymes to at least partially digest the amnion tissue, (3) the step of removing the undigested amnion tissue, and (4) the step of culturing the enzyme digested amnion fraction comprising MSCs (see p. 5, col 1, [0085-0094]).
However, Yamahara and Muraki are silent to the buffer being a balanced saline solution such as HBSS.
In regard to claims 8 and 12, Ganchas-Soares teaches a method for the hypothermic preservation of human MSC (i.e., from umbilical cord) at 2°C to 8°C for 48 hours in a balanced salt solution that comprises glucose, such as HBSS for the transportation to the laboratory (p. 14, last para., p. 15, 1st para., p. 21, 1st para.).
Accordingly, it would have been obvious to practice to one of ordinary skill at the time of filing to practice the method of Yamahara comprising the hypothermic storage step in a buffer, and substitute the balanced salt solution of PBS for the balanced salt solution comprising glucose such as HBSS as taught by Ganchas-Soares with a reasonable expectation of success. One of ordinary skill would have been motivated to do so as taught by Ra et al. (2013) because using a HBSS buffer is more similar to the constituents of the human body rather than using general PBS (col 10, lines 28-30).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 5/27/2026 are acknowledged and have been addressed above.
Pertinent References
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure is the following: Abazari et al. (Cell Gene Ther Insight, 2017, 857-871) evidences that during hypothermic storage, increased membrane leakage combined with cold-induced dysfunction of membrane pumps, result in perturbation of intracellular ionic balance that can initiate apoptotic and necrotic pathways in stored cells (see p. 864, Introduction, last para. of Abazari).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm.
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/ARTHUR S LEONARD/ Examiner, Art Unit 1631
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