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 .
Claim Objections
Claim 4 is objected to because of the following informalities: the claim states, “Lympho-myeloid nich cell”. Correction of spelling required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
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.
Claims 1 and 10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 and 10 recite the limitation "the supplements cell culture medium" in line 2 of claim 1, and line 3 of claim 10. There is insufficient antecedent basis for this limitation in the claim. What is/are the supplements? It has not been defined in the claim or the specification. This equivocal interpretation leaves the metes and bounds of the claims unclear. (MPEP 2173.02. See Packard, 751 F.3d at 1311, 110 USPQ2d at 1787).
The claims read, “do not exceed 50% of the composition”. It is unclear what components are not to exceed 50% of the composition. Is it each individual component (serum, thickener, media) that should not exceed 50% or is the combination of all those components that should not exceed 50% of the composition? This leaves the metes and bounds of the claims unclear. (MPEP 2173.02. See Packard, 751 F.3d at 1311, 110 USPQ2d at 1787).
Claim 2 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The applicant states in the preamble, “the therapeutic product of claim 1” and then attempts to further limit the claim with, “wherein the cell culture medium used for growing the cells” which constitutes a different statutory class (product and method style language). The applicant may re-write the claim as “the therapeutic product of claim 1, wherein the cell culture medium is selected from MEM, DMEM, F12, DMEMIF12, IMDM, M-199, RPMI medium, serum free medium, T cell medium, stem cell medium, keratinocyte culture medium, cell specific culture medium, normal saline, ringer lactate solution, phosphate buffered solution, balanced salt solution and combination thereof.”
Claims 5 and 7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 5 states, “wherein the thickener is any one of synthetic polymers and natural polymers to prepare gel.” And claim 7 states, “wherein the antibiotics used for preparing the cell based therapeutic gel product”. The phrases “to prepare gel” (claim 5) and “used for preparing the cell based therapeutic gel product” (claim 7) render the claim indefinite because they imply a method type claim. The applicant my rewrite claim 5 by omitting the phrase “to prepare gel” and claim 7 by omitting the phrase, “wherein the antibiotics used for preparing the cell based therapeutic gel product”. (MPEP 2173.02. See Packard, 751 F.3d at 1311, 110 USPQ2d at 1787).
Claim 8-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 8, step f) reads, “maintaining the adherent cells in Lympho-Myeloid Niches (LMN), macrophages, lymphocytes, dendritic cell, endothelial cells, progenitor cells, and stem cells for long term…”. It is unclear what/where the adherent cells are maintained. The claim reads as if adherent cells are maintained inside macrophages, lymphocytes, dendritic cell, endothelial cells, progenitor cells, and stem cells. This leaves the metes and bounds of the claim unclear. (MPEP 2173.02. See Packard, 751 F.3d at 1311, 110 USPQ2d at 1787).
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 1-7, 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2022092307 A1, effective filings date 10/30/2020, further in view of WO2017076782A1, published 05/11/2017, and Xiang Ping, et al (2023), and supported by Zhang, M 2012.
WO 2022092307 A1 discloses, “According to one aspect, a hydrogel fiber includes a hydrogel encapsulating mesenchymal stem cells.” (paragraph 0010), and, “According to one preferred aspect, the base material contains collagen …” (paragraph 0012). Furthermore, “According to one preferred aspect, the hydrogel contains calcium alginate or barium alginate.” (paragraph 0014). Additionally, “For example, the base material may contain penicillin-streptomycin as the antibiotics.” (paragraph 0108). They go on to outline the preparation of a potential hydrogel composition, “First, a core solution, a hydrogel preparation solution, and a gelling material were prepared… Furthermore, “The core solutions in Examples 1-2, 2-3, 2-4, and 4-2 and Reference Example 3-1 are a medium. The medium is obtained by adding fetal bovine serum (FBS) and an antibiotic to a GlutaMAX medium (MEM α, nucleosides, GlutaMAX™) (manufactured by Thermo Fisher Scientific Inc.: Cat No. 32571-036). The GlutaMAX medium is obtained by adding GlutaMAX supplement to αMEM.” (paragraph 0156). Importantly, they disclose the potential applications of the disclosed hydrogels, “According to one preferred aspect, the hydrogel fiber is for at least one of suppression of fibrogenesis, suppression of inflammatory cell infiltration, and tissue repair and regeneration.” (paragraph 0017). WO 2022092307 A1 does not disclose the use of Lympho-Myeloid Niche cells in their hydrogel composition.
WO2017076782A1 discloses, “The current disclosure provides, inter alia, a composition {e.g., an engineered biomaterial) including ECM components of a mammalian tissue and a polymer for application to a wound…” (paragraph 0006). Furthermore “In mammals, ECM often comprises about 90% collagen, in its various forms. (paragraph 0023). Additionally, “The composition of the present disclosure (e.g., an engineered biomaterial) includes peripheral blood mononuclear cells (PBMCs).” (paragraph 0057).
Importantly, both references disclose collagen-based hydrogels infused with cells. Furthermore, both disclose hydrogels for use in wound healing/tissue repair and WO2017076782A1 discloses using PBMCs specifically in wound healing (a therapeutic endeavor). Thus, WO2017076782A1 provides a suggestion/motivation to combine PBMC cells with the hydrogel disclosed in WO 2022092307 A1 for the purpose of treating wounds. Therefore, it would have been obvious to one of skill in the art, before the effective filing date, to combine the hydrogel composition of WO 2022092307 A1 with PBMCs in place of hematopoietic stem cells in the treatment of wounds.
The suggestion/motivation to combine PBMC cells with a hydrogel renders claim 1 obvious because the combination details a collagen-based hydrogel gel containing serum (FBS), media (MEM), an antibiotic (pen-strep), a thickener (alginate), and PBMC cells. Importantly, PBMCs are known to differentiate into myeloid and lymphoid types as evidenced by Zhang, M 2012. This disclosure reads on the claims because the specification of the current application discloses LMNs as lymphoid and myeloid cells made from PBMCs. Thus, it would have been obvious to differentiate these cells to obtain LMN cells. It is important to note that while the specific limitations of “1- 50% cell culture medium, 1- 50% plasma or serum, 1-5% antibiotics, and thickener, wherein the supplements cell culture medium, plasma or serum, antibiotics, and thickener do not exceed 50% of the composition.” are not explicitly disclosed in the references, they can be treated as results-effect variables.
Xiang Ping, et al. (2023) details the optimization of hydrogel components such as alginate concentration, polymer concentration (aka agarose), and ionic strength.
Therefore, Xiang Ping, et al. provides explicit teachings/motivations to optimize the different hydrogel components to achieve the aforementioned claimed limitations. It illustrates that such optimization would have been a matter of routine experimentation. Thus, it would have been obvious to one of skill in the art to optimize the various concentrations that make up the gel.
In the case of a result-effective variable, the discovery of an optimum value of the variable in a known process is ordinarily within the skill of the art. Where 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. Therefore, it would have been obvious to one of ordinary skill in the art to determine through routine experimentation the optimum or workable ranges of parameters such as serum, media, and thickener concentrations since these variables would have been recognized as result-effective. (MPEP2144.05(II)). See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claim 2 is rendered obvious as WO 2022092307 A1 defines the media as MEM. Claim 3 is rendered obvious by the fact that the serum is from an animal origin (FBS). Claim 4 is rendered obvious because PBMC cells are known to differentiate into macrophages, lymphocytes, dendritic cell, endothelial cells, progenitor cells, and stem cells. (Zhang, M 2012). Claim 5 and 6 are rendered obvious because the thickener used (alginate) is a natural polymer (claim 5) and a carbohydrate (clam 6). Claim 7 is rendered obvious because the antibiotic used is pen-strep.
As referenced above, all the limitations of claim 1 were addressed and rendered obvious. Claim 10 is to a method of chronic wounds in a subject in need thereof comprising applying therapeutic gel composition to the chronic wound which comprises “lists the same components of the composition outlined in claim 1.”
WO 2017076782 A1 discloses a method of treating a wound with a collagen-based gel infused with cells to achieve therapeutic benefit. “The present disclosure provides that the addition of human cells to the gel prior to wound application… The healing of a wound, for example, skin tear, friction, closed impact surgical wound, skin abrasion, burn (first-degree, second-degree, and/or third-degree), skin incision, skin laceration, skin contusion, skin puncture, pressure ulcer, venous ulcers, arterial ulcers, neuropathic/diabetic wounds, lymphedema, or surgical site incision…” (paragraph 0066). Furthermore, WO 2017076782 A1 also clearly outlines the advantages of using PBMC infused hydrogels for the treatment of wounds in animal subjects. “Clear differences were observed with regards to wound closure in animals treated with PSG only and PSG+hPBMC. By 15 days, the wounds in these animals represented the most significant difference in wound closure. Already on day 15, complete wound closure was observed in 5/6 (83%, p<0.05) mice treated with PSG+hPBMC, and in 4/6 (66%, p<0.05) mice treated with PSG only as compared to 0/3 (0%) in untreated and mice treated with HA. On day 25, complete wound healing was observed in all groups. The healed skin in animals treated with PSG only and PSG+hPBMC was similar to normal skin, while an elongated scar was still observed in the healed skin of the control groups due to excessive contraction” (paragraph 0111). Importantly, it is known that PBMC cells are the progenitors for all of the cells in the Lympho-Myeloid Niche.
As established above, WO2017076782A1 provides a suggestion/motivation to combine PBMC cells with the hydrogel disclosed in WO 2022092307 A1 for the purpose of treating wounds. WO 2017076782 A1 goes on to disclose a method for treating chronic wounds using a therapeutic gel composition, including a “surgical wound”. Therefore, WO 2017076782 A1 provides a clear suggestion/motivation to use the composition of claim 1 (which is identical the composition outlined in the method of claim 10) in the treatment of chronic wounds, including surgical wounds. This renders claim 10 and claim 11 obvious.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over WO-2022092307-A1 and WO2017076782A1 as applied to claim 1 above, and further in view of Burdiati et al. 2020, Grzesik et al. (7/15/2021), and Mammalian Cell Culture: Subculturing (2/06/2019).
As rationalized above, WO 2022092307 A1 and WO2017076782A1 render the composition of claim 1, also referenced in step h) in claim 8, obvious.
Burdiati et al. 2020 discloses the process of obtaining blood samples from subjects, density gradient centrifugation of the blood using ficoll, and resuspending the isolated PBMCs in RPMI 1640 media supplemented with fetal bovine serum (preparation of PBMCs). They then go on to count the cells and subsequently transferring them to a culture vessel under 37C and 5% CO2. They outline the long-term culture of PBMCs by collecting the cells, centrifuging, and changing to fresh media. (culture of PBMCs). Burdiati et al. 2020 does not disclose the process for removal of adherent cells using dissociating reagents.
Mammalian Cell Culture: Subculturing (2/06/2019) discloses the use of a dissociation reagent, in particular trypsin, to remove adherent cells from the culture vessels (page 4, section “Trypsinize”).
Burdiati et al. 2020 discloses a well-known and general method of obtaining PBMCs from veinous blood while Mammalian Cell Culture: Subculturing discloses a well-known and general process of trypsinizing/passaging adherent cells. Thus claim 8 is the result of combining known elements to produce expected results. Therefore, claim 8 is obvious. Furthermore, the dissociation reagent used is trypsin, which renders claim 9 obvious.
It is important to note that while the specific limitations in claim 8, 20% FBS concentration used, and 2-3 days between media changes are not explicitly disclosed in the references, they can be treated as results-effect variables.
Grzesik et al. (7/15/2021) details the optimization of culture media composition and protocol parameters in cell culture.
Therefore, Grzesik et al. (7/15/2021) provides explicit teachings/motivations to optimize culture media composition and protocol parameters to achieve the claimed limitations of 2-3 days in culture and 20% FBS. It illustrates that such optimization would have been a matter of routine experimentation. Thus, it would have been obvious to one of skill in the art to optimize culture media composition and protocol parameters to achieve the aforementioned claim limitations. (MPEP2144.05(II)). See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Conclusion
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/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638