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 .
Claims 17-18,21,27,29-34,36-37,54, and 60-61 are under examination.
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.
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 17-18,21,27,29-34,36-37,54,60-61 are rejected under 35 U.S.C. 103 as being unpatentable over Bai “Restraint of the Differentiation of Mesenchymal Stem Cells by a Nonfouling Zwitterionic Hydrogel” Angew. Chem Int Ed. 2014, 53, 12729-12734 in view of Vannier (WO 2011161174)
Bai teaches a method for protectively storing a population of cells (multipotent stem cells) in a matrix comprising a zwitterionic microgel/hydrogel to provide stored cells, wherein the stored cells retains their biological function on storage (Abstract, Figure 2). Figure 2 shows that the microgel/hydrogel encapsulation/co-mingle process can store cells.
Bai fails to teach releasing the stored cells from the matrix by washing through a size-limiting membrane to provide released cells having substantially retained biological function and zwitterionic microgels with which the cells are comingled during storage. However, Vannier teaches the release of stored cells from a matrix by using a combination of dilaceration, enzyme application, and washing through a size-limiting membrane (a filter) to provide released cells having substantially retained biological function and microgels with which the cells are comingled during storage (Vannier--Pages 2-3).
It would have been obvious to an artisan of ordinary skill at the time of effective filing to have used the cell release method of Vannier to release and thus harvest the cells present in the microgels of Bai. An artisan would have been motivated to have released the cells from the matrix of Bai using a filter by washing them as taught by Vannier in order to successfully isolate out the useful therapeutic cells of Bai (Vannier--Page 3, ln 15-22) so that such therapeutic cells remain viable to be used in applications such as cell therapy, biomaterial, and tissue engineering (Abstract of Vannier). There would have been a reasonable expectation of success using the method of Vannier to harvest the cells in the microgel of Bai because Vannier’s method, “does not damage cells and provides cells that are healthy, viable, and fully functioning (Vannier--Page 2, ln 23-24) as in instant Claims 17-18.
Dependent Claims taught by Bai
There is no requirement that a cryoprotective agent be present (Abstract, Figure 2) as in instant Claim 21. The zwitterionic microgel comprises a crosslinked polymer having crosslinks formed by zwitterionic bonds (Page 12729) as in instant Claim 29. The zwitterionic microgels have polycarboxybetaine crosslinks which are degradable (Page 12729, rt column) as in instant Claim 30. The zwitterionic microgel has a crosslinked polycarboxybetaine (Page 12729, rt column) as in instant Claim 31. The crosslinked zwitterionic polymer is prepared by a polymerization of a polymerizable carboxybetaine (Page 12729, rt column) as in instant Claim 32. Bai teaches wherein the zwitterionic microgel consists of a crosslinked zwitterionic polymer (Page 12729, rt column) as in instant Claim 33. Bai teaches a zwitterionic microgel is composed of monomers having separate positively and negatively charged groups so the zwitterionic microgel taught in Bai teaches the limitation. Because there are mixed charges, the crosslinks present are formed by an association of a portion of one mixed charge copolymer with another (Page 12729, rt column) as in instant Claims 34,36-37.
The zwitterionic polymers of Bai inherently have diameters. Bai does not specifically state what the diameters are. However, MPEP § 2144.05 (II) states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int' l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
A review of the specification fails to provide evidence that the clamed diameters of polymers are critical. Absent such evidence it would have been obvious to an artisan of ordinary skill at the time of effective filing Bai to try a finite number of different diameters (which would impact concentration of polymer and concentration of cells that can be encapsulated) to predictably arrive at the claimed diameter range. This would allow Bai to predictably arrive at the claimed diameter through routine optimization. Thus, Bai renders the instantly claimed diameter ranges as in instant Claims 27,34,60-61.
Dependent Claims taught by Vannier
As mentioned above, Vannier teaches releasing the cells from a matrix scaffolding (Pages 3-4). The claims do not require an active expansion step. All that is required is protective and reversable storage as in instant Claim 54. Vannier teaches that copolymers can be used in hydrogel formulations (Suitable 3D Hydrogel Matrices Section) as in instant Claims 34,36-37.
Bai teaches encapsulating (storing) cells in a microgel. Bai does not teach how to release the cells from its microgels by washing the microgels. Vannier teaches a combination of methods including washing (Page 3) that can be used to remove cells. The ordinary skilled artisan seeking a method to complement the invention of Bai would have been motivate to have used the method of Vannier to release the cells in order to successfully harvest the target cells (Page 3 of Vannier). It would have been obvious for the skilled artisan to do this because of the known benefits associated with harvesting desirable target cells (Page 3 of Vannier). Given the teachings of the cited references and the level of skill of ordinary skilled artisan at the time of applicants’ invention, it must be considered, absent evidence to the contrary, that the ordinary skilled artisan would have had a reasonable expectation of success in practicing the claimed invention.
All of the claimed elements were known in the prior art, and one skilled in the art could have combined the elements 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 the invention (See KSA International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007)). People of ordinary skill in the art will be highly educated individuals, possessing advanced degrees, including M.D.'s and Ph.D.'s. They will be medical doctors, scientists, or engineers. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in cell culture, microgel/hydrogel culture, and microgel/hydrogel formation. Therefore, the level of ordinary skill in this art is high.
Response to Applicants Arguments/Amendments
Applicants argue that the amendments now claim that the zwitterionic microgels and the stored cells are comingled, such that the zwitterionic microgels present during the storage step survive the release step intact. Applicants argue that neither Bai nor Vennier, alone or in any proper combination include each element claimed.
The examiner was not persuaded by the argument that Bai does not teach a structure in which the zwitterionic microgels and stored cells comingled. The definition of comingle can merely mean to combine according to Merriam Webster. Furthermore, applicants’ specification recites “a comingle microgel storage method in which the platelets are mixed with representative zwitterionic microgels of the invention (PCB microgels) to limit aggregation and non-specific interactions.” This section fails to further state how the aggregation is limited specifically or compared to a specific type of interaction. The section in the specification also states that non-specific interactions are limited.
Figure 2 of Bai shows comingling because microgel/hydrogels are indeed combined with cells. Non-specific interactions are indeed limited in Figure 2 of Bai since the cells have limited interaction with the environment outside of the hydrogel encapsulation. Both the specification and the teachings of Bai use carboxybetaine monomers to create their desired gels, therefore, the gel of Bai would be expected to behave the same as applicants’ claimed microgel.
Applicants further argue in italics, “Bai describes the formation of 3D cell-hydrogel constructs from a solution that “was placed between two glass slides separated by 1.5 mm-thick polytetrafluoroethylene spacers and allowed to polymerize in a crosslink oven.” Bai SJ, page 3. The Bai Supporting Information is submitted herewith as Exhibit A and is attached to this response. Applicant respectfully submits that a person of ordinary skill in the art would recognize that a typical glass slide has dimensions of roughly 76 mm x 25 mm, thus making the hydrogel of Bai on the order of 76 x 25 x 1.5 mm. The analysis described in Bai further includes removing “a 20- um slice of the hydrogel from the surface,” and then that “[t]here sections were sampled every 250-300 um across the depth of the hydrogel.” Bai ST, page 8.”
The actual formation of the 3D hydrogel construct including whether or not two glass slides were used is not mentioned in the instant set of claims. For example, instant claim 17 focuses on cells comingled with microgel being used for storage, not a method of making such a gel. The actual gel size is not mentioned in the claims. Some dependent claims only mention size in reference to a polymer’s diameter.
Applicants further argue, “Bai not only fails to describe the releasing of stored cells from the matrix by washing, but Bai further fails to describe stored cells comingled with zwitterionic microgels at least because any cell storage in Bai occurs in bulk hydrogel form.”
Bai is not relied upon to teach releasing the stored cells from the matrix by washing. The secondary reference, Vannier, is relied upon to teach the release of the cells by washing them. Applicant argues that Bai does not teach comingling of cells with the microgel because the cell storage in Bai “occurs in bulk form.” The encapsulation of the cells as shown in Figure 2 of Bai would still be considered comingling since the microgel and the cells are combined. Furthermore, the claims do not address bulk form and/or specifically state how the cells are arranged in relation other cells in the gel. The claims do not address whether the cells are isolated or aggregated. If the cells are isolated cells, then examiner feels such a limitation could be used to distinguish the invention from the Bai reference.
Applicant argues the application of Vannier’s filtration/membrane treatment. The following is quoted from applicant in italics.
Applicant respectfully notes that at page 20, lines 10-16, “Vannier describes that
prior to use, the lyophilized hydro gels were cut into rectangular parallelepipeds ( about 5 x 5 x 1.5 mm). The cut hydrogels were then sterilized at 100°C for 1 hour using an oil bath. The hydro gels were then immersed in pure ethanol and manually compressed to eliminate air trapped within the hydrogel structure. The hydro gels were then rehydrated using a cell culture medium (e.g., 15 RPMI (Euro bio) comprising antibiotics) until they swelled by a 100-fold in volume.
Applicant further states, “At page 11, lines 15-16 (emphasis added), Vannier further describes that One skilled in the art will know how to select a filter that physically blocks the fragments of the hydrogel matrix but allows cells through. Thus, Applicant respectfully submits that Vannier describes 1) the formation of large (5x5x1.5 mm) hydrogels for enclosing cells, and 2) a filtering step wherein a filter blocks the fragments of the original hydrogel matrix formed by Vannier’s dilaceration step.”
“In the present application, on the other hand, and as noted above, Claim 17 clarifies that the starting zwitterionic microgel material is comingled with the stored cells, the releasing step washes the stored cells from the zwitterionic microgels, and thus that the zwitterionic microgels filtered out in the washing step are the same zwitterionic microgels that were comingled with the stored cells. In this manner, amended Claim 17 clarifies that the zwitterionic microgels survive the process intact, without being broken apart, such that they may be recovered by washing through the size-limiting membrane.”
There is nothing in the instant set of claims that preclude cutting the microgel. The claims also do not rule out the rehydration of the microgels. The claims only state, “storing a population of cells in a microgel matrix comprising zwitterionic microgels to provide stored cells comingled with the zwitterionic microgels, wherein the stored cells substantially retain their biological function on storage, and releasing the stored cells comingled with the zwitterionic microgels from the matrix by washing through a size-limiting membrane to provide released cells having substantially retained biological function, and the zwitterionic microgels with which the cells are comingled during storage.” Figure 2 of Bai shows that the cells and microgel are combined (comingled) during storage. The instant claims do not clarify if the cells and microgel remain together or are separated on the size limiting membrane. The limitation just states providing, “released cells having substantially retained biological function, and the zwitterionic microgels with which the cells are comingled during storage.” There is no further limitation that recites if the cells and/or the microgels stay on the membrane or are rinsed off of the membrane. The claim limitation does not state that the microgel remains intact and is not broken apart.
Argument Regarding claims 27,34, 60-61
Applicants better explained Figure 3 of the Bai reference; the Bai reference was authored by applicants. The examiner was persuaded that claims 27,34, and 60-61 were not taught in Figure 3. Therefore, examiner has decided to make this action non-final and put forward a different argument regarding those claims.
The examiner feels that it would be helpful to add some additional structure limitations to the microgel recited in the claims. For example, the brief drawing description mentions different types of carboxybetaine monomers that can be used (CB-1, CB-2, PCB-1, PCB-2) which employ a crosslinker such as CB-X. Many of these monomers were not mentioned in the Bai reference. Furthermore, indicating whether the cells are isolated cells or aggregated cells within the microgel would be helpful as well.
Conclusion
All claims stand rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN K VAN BUREN whose telephone number is (571)270-1025. The examiner can normally be reached M-F:9:30am-5:40pm; 9:00-10:00pm.
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LAUREN K. VAN BUREN
Examiner
Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638