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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 29th, December, 2025 has been entered.
Claim Status
Claims 1, 8-9, 11-18, 20, 24-25 and 27 are pending.
Claims 1, 8-9, 11-18, 20, 24-25 and 27 are under examination.
Maintain Claim Rejections - 35 USC § 112(a)
Scope of Enablement
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.
Claims 15-18 and 20 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method for harvesting and subsequent passaging of human pluripotent stem cells comprising: incubating the human pluripotent stem cells in the formulation of claim 1 in a cell culture plate or vessel with agitation for about 30 to 40 minutes, wherein said human pluripotent stem cells detach from the cell culture plate or vessel as single cells having cell viability of 80% to 84.2% and wherein no more than about 15% of the human pluripotent stem cells are aggregated cells after detachment
does not reasonably provide enablement for:
cell viabilities above 84.2%
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the methods the invention commensurate in scope with these claims.
Wands Factors
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 Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). 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. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
Breadth of the Claims
Instant claims encompass:
“cell viability of at least 80%”
The broadest reasonable interpretation of the scope of this genus encompasses from 80% and up to 100% viability which includes no cell death whatsoever during passaging.
Direction or Guidance Presented
“at least 80% viability”
While contemplating at least 80% viability (para. [0003-0004, 0007, 0016, 0030, 0036, 0045, 0047, 0049, 0059, 0065, 0072, 0075, 0081, 0087, 0092, 0095, 0098, 00101]), the specification provides limited guidance on obtaining high viabilities (Examples 1-3 and 5).
Present Working Examples
Example 1 (para. [0086-0087])
In example 1, cell passaging solutions were tested for the following formulations:
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L7 Formulation 3 consistently generated less than 5% of cell aggregates when compared to L7 Formulation 1 and 2.
L7 Formulation 3 consistently resulted in a high viability of 90% or higher when compared to L7 Formulation 1 and 2
L7 Formulation 3 maintained morphology of pluripotent stem cells in culture, using two different PSC lines (H1 and HEUS8).
Example 2 (para. [0088-0093])
The Formulation 3 passaging solution was compared with enzymatic and alternative non-enzymatic cell detachment solutions in different pluripotent stem cell lines and cell culture systems comprising of various mediums and matrices.
Three cell lines were used (H1, WA27, and HAD106 human embryonic stem cell lines).
WA27 cells passaged using Formulation 3 passaging formulation produced comparable individualized cells and comparable or higher cell attachment when compared to enzymatic passaging TrypLE regardless of the cell culture medium (Figure 3).
The use of Formulation 3 as a passaging formulation results in a significantly higher cell growth after passaging (Figure 4).
Formulation 3 was found to result in superior or comparable viability, total cell number, or percentage of aggregates generated after dissociation / passaging when compared to enzymatic passaging TrypLE.
Results are summarized in Table 4, which is copied below.
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Example 3 (para. [0094-0096])
In example 3, Formulation 3 was compared against other dissociation treatments in suspension culture.
The results show acceptable level of cell fold expansion (around 4-5 fold), percentage of aggregates remaining in the culture (6-12 %), aggregate size (about 150-200 microns in diameter) following passaging of the cells using L7 Formulation 3 (Table 5: copied below).
Depending on the treatment, the viability was between 80-84 % for the cell treated with L7 Formulation 3.
Further optimization of the treatment with L7 Formulation 3 was carried out by increasing the incubation time (from 15 min to 20, 30, and 40 min) and using agitation inside the spinner flask and results are summarized in Example 5 and Figure 8.
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Example 5 (para. [00101-00102])
Optimization was performed to show L7 Formulation 3 can reduce the number of aggregates seen in the culture using 40 min incubation time in a 3D bioreactor. Results are in Figure 8 and Table 9 (copied below).
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Absent Working Examples
“at least 80% viability”
No working example is provided with a cell viability of 84.3% to 100%. The highest reported cell viability of any method disclosed using formula 3 with the required claim limitations is 84.2% (Table 5).
State of the Prior Art and Unpredictability of the Art
Cell Viability
Regarding cell viability, Applicant is directed to the art of record of Nie et al. (PLoS One. 2014 Jan 30;9(1):e88012. eCollection 2014.; see IDS filed 31st, October, 2019; henceforth “Nie2”). Nie2 evidences viability of cells passaged a single cells in unpredictable. Specifically, Nie2 evidences the continuous cultivation of adherent hPSCs from single cells may play a role in promoting chromosomal abnormalities and genetic alterations and Nie2 evidences single cells produced during the subculture of hPSC colonies are susceptible to dissociation-induced apoptosis (Introduction pg. 1 col. 1 1st para.). Nie2 further evidences that even passaging as aggregates results in the highest post-detachment cell viability of only 97% (abstract).
Regarding cell viability, Applicant is additionally directed to the art of Beers et al. (Nat Protoc. 2012 Nov;7(11):2029-40. Epub 2012 Oct 25.; henceforth “Beers”). Beers evidences viability of cells passaged as single cells is unpredictable. Specifically, Beers evidences human ESCs survive poorly after individualization (i.e., being made single cell), because these cells are more sensitive to treatments and are prone to cell death (Introduction pg. 2029 col. 1 2nd para.).
Regarding cell viability, Applicant is additionally directed to the art of Chen et al. (Cell Stem Cell. 2014 Jan 2;14(1):13-26.; henceforth “Chen”). Chen evidences passaging human induced pluripotent stem cells (hPSC) as single cells is unpredictable. Specifically, Chen evidences that hPSCs have a drastic loss of viability after enzymatic dissociation as single cells. Thus, the hPSCs are generally plated as clumps and grow as colonies and aggregates (pg. 13 col. 2 2nd para.).
Lasty, Applicant is directed to the post-filing art of Cruvinel et al. (SAGE Open Med
. 2020 Oct 22:8:2050312120966456. eCollection 2020.; henceforth “Cruvinel”). Cruvinel evidences that even post-filing it was well-recognized in the art that single-cell passaging is usually followed by great loss of cellular viability, and also promotes rapid selection of genetically abnormal clones (pg. 12 col. 1 last para.).
Thus the art before the effective filing date of the claimed invention teaches methods of single cell passaging were highly unpredictable, with challenges of low viability and genetic abnormalizes of passaged cells.
Unpredictability of the Art and Quantity of Experimentation Necessary
As the arts of Nie2, Beers, Chen and Cruvinel demonstrate above, the obstacles that hinder the use of the claimed method to obtain the functional result of viabilities above 84.2% are not easy tasks to be done or solely routine experimentation to enabled particular embodiments of the claimed method.
Further, Applicant’s own arguments evidence the vast quantity of experimentation required to arrive at a method of passaging single cells. Applicant states “a skilled artisan seeking to develop
compositions for harvesting and passaging single cell human stem cells would begin the
endeavor of developing a formulation for harvesting and passaging single cell human stem cells
without guidance. Such an undertaking would involve screening a massive design space:
thousands of salts and buffers can be combined at concentrations spanning their respective full
solubility ranges to generate a virtually infinite number of combinations. Common incubation
times for different general cell culture protocols range from seconds to hours, adding an
additional dimension of variability. A person of ordinary skill in the art would have understood
that screening the full breadth of such a wide range of conditions would be difficult” (Remarks filed 8th, October, 2024; pg. 12).
The type of experimentation required for one of ordinary skill to arrive at the claimed methods would require new methodologies. This level of experimentation goes beyond what would be routine optimization know at the time of filing. As such, the amount of experimentation would be undue.
The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112(a) requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to practice the instant broadly claimed invention.
Conclusion
In conclusion, the breadth of the claims lack enablement because the specification provides limited working examples with viabilities of 80% up to 84.2%. The art at the time of effective filing fail to provide specific guidance that supplement to shortcomings of the specification and further teaches that the breadth of claims cannot predictably be performed to arrive at the claimed functional results. Further, a great deal of new methodology would need to be developed to enable the full breadth of the claims and this level of experimentation is undue.
Response to Arguments
Applicant’s arguments, filed 29th, December, 2025, have been fully considered but are not found persuasive.
Applicant argues “The Applicant has demonstrated hPSC culture with Formulation 3 resulting in cell viability higher than 84.2% in Example 4, Table 6 of the specification as filed. Furthermore, results shown in Example 2, Table 4 also demonstrate corrected cell viabilities higher than 84.2%. The Office seems to focus on the results demonstrated in Example 3 and Table 5, which described the use of Formulation 3 in suspension culture. However, claims 15-18 and 20 are not specific to suspension culture and therefore the cell viabilities demonstrated with Formulation 3 in Examples 2 and 4 are also relevant.
In response, Example 4, Table 6 of the specification is copied below for reference:
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This table does include Formula 3, but the formula also has FGFb added, which is not a requirement of instant claims and therefore the viability data in Example 4, Table 6, is not commensurate in scope with instant claims. The formulations discussed above are unpredictable for cell viabilities for the reasons of record above. Furthermore, the viability data in Example 4, Table 6 also still does not support cell viabilities above 94.932% in view of the state of the art above which evidences that cell viability for single cell passaging is not predictable.
Applicant respectfully submits that a person of ordinary skill in the art could practice the
method of present claims 15-18 and 20 claims without undue experimentation, as evidenced by
the data provided in the specification, and have a reasonable expectation of achieving cell
viabilities greater than 84.2%. Applicant therefore further submits that the current claim
language is enabled in the specification as filed based on at least the data provided in Examples
2, 3, and 4.” (pg. 6).
In response to Applicant’s arguments, arguments of counsel cannot take the place of
factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145
USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed.
Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus, Attorney statements that a person of ordinary skill in the art could practice the method of present claims 15-18 and 20 claims without undue experimentation, as evidenced by the data provided in the specification, and have a reasonable expectation of achieving cell viabilities greater than 84.2% are not evidence without a supporting declaration.
Regarding Examples 2, 3, and 4, Example 2 does not provide cell viability data. Example 3 does provide cell viability data, but this example only shows data up to 84.2% and the state of the art above evidences cell viabilities for single cell passaging are not predictable. Regarding Example 4, as discussed above, the formulations of example 4 have FGFb added at specific amounts which is not a requirement of instant claims and therefore this data is not commensurate in scope with the instant claims and cannot support higher cell viabilities because the state of the art evidences they are unpredictable, and because Applicants Example 3 indicates cell viabilities above 84.2% were not achieved in an example where specific amounts of FGFb were not added.
Withdrawn Claim Rejections - 35 USC § 112b
The rejection of claims 1, 8-9, 11-18, 20, 24-25 and 27 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite because the term “about” precedes each value defining a range is withdrawn in view of Applicant’s arguments.
Maintained 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.
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.
Claims 1, 8-9, and 11-14 remain rejected under 35 U.S.C. 103 as being unpatentable over Nie et al. (WO 2012/158899 A1; see IDS filed 31st, October, 2019; henceforth “Nie”).
Regarding claim 1, Nie discloses a formulation (Solution 2; Figure 13) comprising:
15 mM sodium citrate (“SC concentration (15mM)”)
a salt comprising 135 mM KCl; and
Ca2+Mg2+-free Dulbecco's phosphate buffered saline (DPBS); (pg. 14; tables 2-3; claims 1-8 and 12)
wherein said formulation has an osmolarity of 299 mOsmol/liter (“Osmo (actual)” Specifically the embodiment of “Solution 2”; Figure 13).
However, regarding claim 1, although Nie discloses the formulation comprises comprising 135 mM KCl, Nie does not disclose the solution comprises about 120mM KCl.
Nevertheless, regarding claim 1, Applicant is reminded that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close (see MPEP section 2144.05 and Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985))
Therefore, regarding claim 1, one of ordinary skill would not consider the difference between the claimed formulation with about 120mM KCl, which encompasses up to 3% variability and therefore encompasses 123.6 mM KCl, and the 135 mM KCl disclosed by Nie to be inventive because the values are so close that prima facie one skilled in the art would have expected them to have the same properties (see MPEP section 2144.05 and Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)). Additionally, the prior art of Nie appears to evidence that the cell detachment behavior and viability of the solution relies on osmolarity (para. [0094-0096]) and sodium citrate concentration (para. [0098]) (Example 2), and therefore prima facie one of ordinary skill would expect the solution (Solution 2; Figure 13) taught by Nie, which only differs slightly in KCl concentration, but has sodium citrate concentration and osmolarity in the claimed ranges, to have the same properties as the claimed solution.
Furthermore, regarding claim 1, in addition to disclosing the specific value of 135 mM KCl which makes obvious the claimed value of 120mM KCl as discussed above, Nie further teaches specific examples of solutions with KCl concentrations from 68 mM (solution 1; Figure 13) to 540 mM (solution 6; Figure 13) which encompasses a specific range of workable formulations comprising from 68 mM to 540 mM KCl (solutions 1-6; Figure 13).
Regarding claim 1, Applicant is reminded that "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003) (see MPEP 2144.05 (I)). In the instant case, the claimed range of 80 mM to 120mM KCl lies within the broader taught range of 68 mM to 540 mM KCl of Nie (solutions 1-6; Figure 13).
Therefore, regarding claim 1, because the prior art reference of Nie discloses the range of 68 mM to 540 mM (solutions 1-6; Figure 13), which encompasses the somewhat narrower claimed range of 80 mM to 120mM KCl of instant claims, the prior art reference of Nie is also sufficient to establish a prima facie case of obviousness (See M.P.E.P. §2144.05 (I)).
Regarding the KCl concentration of claim 1, applicant is reminded that generally, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II).
Regarding claim 1, it is noted that the wherein clause recites a contingent limitation (i.e. “when human stem cells are harvested and passaged using the formulation with agitation for an incubation time of about 30 minutes to about 40 minutes, the resultant population of stem cells has no more than about 15% aggregated cells”). The broadest reasonable interpretation of a system (or apparatus or product) claim having structure that performs a function, which only needs to occur if a condition precedent is met, requires structure for performing the function should the condition occur (see MPEP section 2111.04 (II)). In the instant case, the structure of the formulation taught by Nie includes a sodium citrate in the claimed range, DPBS, osmolarity in the claimed range, and a KCl of 135 nM concentration that is close enough to the claimed about 120 nM that one of ordinary skill would expect it to have the same properties. Therefore, the structure of the formulation taught by Nie is capable for performing the function should the condition occur and makes obvious instant claims.
Regarding the preamble “for harvesting and passaging single cell human stem cells comprising” of claim 1, the preamble merely states the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation").
Regarding claims 8 and 9, further to the discussion of claim 1 above, a pH of about 7.4 is an inherent property of the formulation of Nie (para. [0026, 0098, 00100]).
Regarding claims 11-13, further to the discussion of claim 1 above, Nie discloses the composition further comprises a human stem cell (instant claim 11), that is an embryonic stem cell (instant claim 12) or an induced pluripotent stem cell (instant claims 12-13) (abstract; para. [0003-7, 0009, 0011-12, 0015-24, 0027, 0029, 0069, 0075, 0086] ; Example 1; claim 3).
Regarding claim 14, further to the discussion of claims 1 and 11 above, Nie disclose the human stem cell is a mesenchymal stem cell (Para. [0063, 00121-00123] Figure 27; Example 7; Claim 1). The mesenchymal stem cells from either a bone marrow MSC, which is a hematopoietic stem cell, or an umbilical cord MSC which is a blood stem cell, would have been immediately envisioned from the limited genus of MSCs.
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 29th, December, 2025 have been fully considered but are not found persuasive.
Applicant argues “The preamble of claim 1 is "necessary to give life, meaning and vitality" to the claim because it is not merely a statement of effect that may or may not be desired, but rather is a statement of the purpose for which the specific combination of ingredients of the claimed formulation is used. Its use in harvesting and passaging single cell human stem cells is further defined in the wherein clause of claim 1. Applicant respectfully submits that the claimed formulation is for "harvesting or passaging single cell human stem cells" and that this recital in claim 1 has both patentable weight and "gives life, meaning, and vitality" to the preamble of claim 1” (pg. 8).
The claim preamble must be read in the context of the entire claim. The determination of whether preamble recitations are structural limitations or mere statements of purpose or use "can be resolved only on review of the entirety of the [record] to gain an understanding of what the inventors actually invented and intended to encompass by the claim" as drafted without importing "‘extraneous’ limitations from the specification." Corning Glass Works, 868 F.2d at 1257, 9 USPQ2d at 1966. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. The preamble of “or harvesting and passaging single cell human stem cells” does not limit the structure of the claimed invention that is fully and intrinsically set forth in the body of the claim because it does not provide or require any additional structure and recites an intended use and therefore the preamble merely states the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction.
It is noted that the remainder of Applicant’s arguments appear similar to those presented in the remarks filed 4th, September, 2025, which the Examiner responded to in the Final Rejection mailed on 30th, September, 2025 pg. 18-23. The Examiner has also responded specifically to the most recent arguments below.
Applicant argues “Nie does not disclose or suggest a formulation as suggested in claim 1” (pg. 8).
In response, Nie suggests and makes obvious the required structural limitations of the claimed invention for the reasons set forth above. As set forth above, the preamble recites an intended use, and the formulation suggested by Nie is capable of meeting the claimed intended use because one of ordinary skill would have expected them have the same properties. Similarly, as set forth above, the wherein clause recites a contingent limitation. In the instant case, the structure of the formulation taught by Nie includes a sodium citrate in the claimed range, DPBS, osmolarity in the claimed range, and a KCl of 135 nM concentration that is close enough to the claimed 120 nM that one of ordinary skill would expect it to have the same properties. Therefore, the structure of the formulation taught by Nie is capable of performing the function should the condition occur and makes obvious instant claims.
Applicant argues “Nie offers no reason to modify its disclosure to achieve the claimed composition and offers the skilled artisan no reasonable expectation that such an endeavor would have been successful. Obviousness requires both a reason to modify the cited art to achieve the claimed invention and a reasonable expectation of success.” (pg. 9).
In response, as stated in the grounds of rejection above, the structure of the product of the claims which is the claimed concentration of sodium citrate, KCl, the presence of DPBS, and the osmolarity are obvious over Nie because the disclosed KCl value of 135 nM of Nie is so close to the claimed value of about 120mM KCl, which encompasses up to 123.6 mM, that prima facie one skilled in the art would have expected them to have the same properties and is further obvious because the prior art reference of Nie discloses the range of 68 mM to 540 mM (solutions 1-6; Figure 13), which encompasses the somewhat narrower claimed range of 80 mM to 120mM KCl of instant claims, the prior art reference of Nie is sufficient to establish a prima facie case of obviousness (see claim 1 rejection above). Therefore, in the absence of factually objective evidence on the record that the claimed ranges are critical, a prima facie case of obviousness exists
In response, regarding reasonable expectation of success, Nie provides some predictability in preparing the composition because Nie teaches preparation of sodium citrate solutions with the claimed components. Applicant is directed to MPEP 2143.02 which states that where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016). In other words, it is the preparation of the modification that requires a reasonable expectation of success. In the instant case, the required limitations are the formulation which comprises the recited components, and Nie provides a reasonable expectation of success in preparing various formulations with the claimed components. As set forth above, the preamble recites and intended use, which is not a claimed limitation, so a reasonable expectation of success is not required for this intended use because it is not a required structural limitation of the claims.
Regarding Applicant’s argument that obviousness requires a reason to modify the cited art, the structure of the formulation taught by Nie includes a sodium citrate in the claimed range, DPBS, osmolarity in the claimed range, and a KCl of 135 nM concentration that is close enough to the claimed 120 nM that one of ordinary skill would expect it to have the same properties and therefore the claimed formulation is not inventive. Furthermore one of ordinary skill would have been motivated to optimize the KCl concentration such as by routine optimization. Applicant is directed to MPEP 2143 which states that the key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious and other rationales to support a conclusion of obviousness may be relied upon by Office personnel. Any rationale employed must provide a link between the factual findings and the legal conclusion of obviousness. In the instant case, the link between the factual findings and the legal conclusion of obviousness, as set forth above, is that the only difference between the limitations of the claimed invention and the formation of Nie is the KCl concentration, and a KCl of 135 nM concentration that is close enough to the claimed 120 nM that one of ordinary skill would expect it to have the same properties and therefore the claimed formulation is not inventive. Furthermore, the prior art of Nie appears to evidence that the cell detachment behavior and viability of the solution relies on osmolarity (para. [0094-0096]) and sodium citrate concentration (para. [0098]) (Example 2), and therefore one of ordinary skill would expect the solution taught by Nie, which only differs slightly in KCl concentration, to have the same properties as the claimed solution because the solution of Nie has sodium citrate concentration and osmolarity within the claimed ranges.
Applicant argues “The Office has not provided a reason for a person of ordinary skill in the art to modify the teachings of Nie for the use of "harvesting or passaging single cell human stem cells," and therefore has not provided a proper prima facie case of obviousness. Applicant respectfully submits that a person of ordinary skill in the art would have no motivation to modify Nie to arrive at the claimed invention, as Nie teaches away from single cell harvesting and passaging of human stem cells” (pg. 9).
In response, the rejection of record above does not allege that one of ordinary skill would modify the disclosure of Nie for the purpose of “harvesting and passaging single cell human stem cells” and therefore arguments directed to this motivation, or alleged teachings away from this motivation, are not pertinent to the present rejection of record.
As stated above, the preamble of “for harvesting and passaging single cell human stem cells” merely states the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02). Further, the wherein clause recites a conditional limitation. As discussed above, the structure of the formulation taught by Nie includes a sodium citrate in the claimed range, DPBS, osmolarity in the claimed range, and a KCl of 135 nM concentration that is close enough to the claimed 120 nM that one of ordinary skill would expect it to have the same properties. Therefore, the structure of the formulation taught by Nie is capable for performing the function should the condition occur.
For products, it is the structure of the product, not the intended use, which is examined against the prior art. If the structure taught by the prior art is capable of meeting the intended use, it meets the claim.
As stated in the grounds of rejection above, the structure of the product of the claims which is the claimed concentration of sodium citrate, KCl, the presence of DPBS, and the osmolarity are obvious over Nie because the disclosed KCl value of 135 nM of Nie is so close to the claimed value of about 120mM KCl, which encompasses up to 123.6 mM due to the “about,” that prima facie one skilled in the art would have expected them to have the same properties and is further obvious because the prior art reference of Nie discloses the range of 68 mM to 540 mM (solutions 1-6; Figure 13), which encompasses the somewhat narrower claimed range of 80 mM to 120mM KCl of instant claims, the prior art reference of Nie is sufficient to establish a prima facie case of obviousness (see claim 1 rejection above). Therefore, in the absence of factually objective evidence on the record that the claimed ranges are critical, a prima facie case of obviousness exists.
Applicant argues Nie teaches away from the invention of the instant claims (pg. 9-10).
In response, Applicant’s arguments are directed to Nie allegedly teaching away from use of the formulations in single cell passaging. However, as set forth above, the preamble of “for harvesting and passaging single cell human stem cells” merely states the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02). Therefore, arguments directed to this motivation, or alleged teachings away from this motivation, are not pertinent to the present rejection of record. The difference between instant claims and the prior art is the exact concentration of KCl, which is made obvious above. Nie does not appear to teach away from this and further Nie specifically teaches ranges which encompass the claimed KCl range.
Applicant argues Nie offers no finite number of predictable solutions and no reasonable expectation that modifying its disclosure would be successful (pg. 10-11).
In response, a finite number of predictable solutions is not relied upon in the rejection of record above and therefore arguments directed to a finite number of predictable solutions are not pertinent to the present rejection of record.
Regarding reasonable expectation of success, Applicant is reminded that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).
Further in response, regarding reasonable expectation of success, Nie specifically evidences at least some degree of predictability in preparing the claimed solution because Nie evidences preparation of sodium citrate solutions with the claimed components as discussed above, and it is well within the level or ordinary skill to adjust concentrations of components in a solution and osmolarity of a solution (see Nie Figure 13).
As stated above, absolute predictability is not required. Applicant is directed to MPEP 2143.02 which states The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016). In other words, it is the preparation of the modification that requires a reasonable expectation of success. Achievement of the desired result, is not necessarily required. In the instant case, Nie evidences guidance preparing sodium citrate solutions with the claimed components and therefore one of ordinary skill would have had a reasonable expectation of success.
Applicant argues the Office relied upon recognition of a problem rather than recognition of a solution (pg. 11-12).
In response, the office does not rely on motivation for modifying Nie for the purpose of harvesting and passaging single cell human stem cells as discussed above, and therefore this argument is not pertinent to the rejection of record.
Applicant argues the claimed ranges are critical (pg. 12).
Specifically, Applicant argues “Example 1 (see [0087]) of the instant application shows that L 7 Formulation 3 generates fewer cell aggregates than L 7 Formulation 1 and L 7 Formulation 2, and Example 2 (see [0088]-[0090]) of the instant application shows that L7 Formulation 3 passaging solution produces "comparable individualized cells and comparable or higher cell attachment when compared to" previously available solutions. Applicant further respectfully submits that examples in a patent application are intended to be demonstrative rather than limiting.” (pg. 13)
In response, although Applicant alleges the claimed ranges are critical, Applicant has not met the criteria to establish the claimed range is critical. First, Applicant’s claim encompasses multiple ranges (sodium citrate amount, salt amount, and osmolarity).
Applicant is directed to MPEP 716.02(d) (II), which states that to establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). In the instant case, Applicant has compared 3 formulations, L 7 Formulation 1-3 (Example 2 para. [0088]-[0090]) and the previous formulation which are copied below for reference:
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Of these formulations, only formulation 3 is within Applicant’s claimed range. More specifically, because Nie teaches the osmolarity and the sodium citrate within Applicant’s claim range, the range in question is the KCl concentration. No tests outside the claim range appear to have been performed or presented regarding the KCl concentration, and therefore, a sufficient number of tests both inside and outside the claimed range have not been shown. Because the only difference between instant claims and the closest prior art of Nie is the KCl concentration, it is this range that must be shown as critical.
Furthermore, criticality of a claimed range is an unexpected result. Therefore, arguments of counsel cannot take the place of factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus,
Attorney statements regarding the unexpected result (criticality of the claimed range) are not evidence without a supporting declaration because the evidence cited in the specification is not sufficient to establish criticality of the ranges for the reasons stated above.
Moreover, regarding the claimed ranges, the only difference between the formulation of instant claims as currently presented, and the specific embodiment of the Solution 2 disclosed by Nie (Solution 2; Figure 13) is the concentration of KCl. MPEP 2144.05 states that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close and prima facie one skilled in the art would have expected the specific embodiment of Solution 2 disclosed by Nie to have the same properties as the claimed solution with 120 nM KCl. Furthermore, the prior art of Nie appears to evidence that the cell detachment behavior and viability of the solution relies on osmolarity (para. [0094-0096]) and sodium citrate concentration (para. [0098]) (Example 2), and therefore one of ordinary skill would expect the solution taught by Nie, which only differs slightly in KCl concentration, to have the same properties as the claimed solution because the solution of Nie has sodium citrate concentration and osmolarity within the claimed ranges. Therefore, in the absence of factually objective evidence on the record that the formulation as claimed does not have the same properties as the specific embodiment of Solution 2 disclosed by Nie, a case of prima facie obviousness exists.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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