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 .
Status of Claims
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This is in response to the papers filed 9 June, 2025. Claims 1 – 6 and 9 – 22 are currently pending. Claim 10 has been amended in the Applicant’s amendment filed 9 June, 2025. No claims have been added or canceled in the Applicant’s amendment filed 9 June, 2025 (Claims 7 – 8 were previously canceled).
Thus, claims 1-6 and 9 - 22 are under examination to which the following grounds of rejection are applicable.
Information Disclosure Statements
The information disclosure statement (IDSs) submitted on 23 July, 2025 have been considered. Initialed copies of the IDSs accompany this Office Action.
Priority
The present application filed November 10, 2021, claims the benefit of PCT/GB2019/050158, filed January 21, 2019 and GB1801014, filed on January 22, 2018.
Thus, the earliest possible priority for the instant application is January 22, 2018.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed 9 June, 2025 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below are herein withdrawn.
Claim Objections
Claim 10 has been amended to properly recite a Markush group. The objection has been withdrawn.
Maintained Objections/Rejections
Claim Rejection - 35 USC § 103
Claims 1-6 and 9 -22 are rejected under 35 U.S.C. 103 as being unpatentable over Connon et al. (hereinafter referred to as “Connon”) (US Patent Application Publication No. US20140072601 A1, published March 13, 2014) and in further view of King et al. (hereinafter referred to as “King”) (King SM et al. Alginate hydrogels for three-dimensional organ culture of ovaries and oviducts. J Vis Exp. 2011 Jun 20;(52):2804. doi: 10.3791/2804. PMID: 21712801; PMCID: PMC3197054.).
Regarding claim 1 (in part), Connon teaches a method for transporting live cells and treating a wound (Abstract). CONNON teaches a method for transporting live cells which are encapsulated or entrapped within hydrogels from a first location to a second location and release of live cells upon reaching the second location (Paragraph [0001]) (interpreted as a method of transporting an in vitro multicellular aggregate from a first location to a second location claim 1 (in part)). CONNON teaches a method for preparing cells for transport (Paragraph [0016], line 6) (interpreted as preparing multicellular aggregate for transportation, claims 1 (in part)). CONNON teaches encapsulating or entrapping the cells in a hydrogel (interpreted as encapsulating in an hydrogel), wherein the hydrogel polymer which is capable of forming a cross-linked or network structure or matrix under appropriate conditions, (paragraph [0016]]) (interpreting a reversible crosslinked aggregate as a multicellular aggregate encapsulated or entrapped; contacting the cells with an alginate hydrogel-forming polymer; polymerizing the polymer to form a reversibly cross-linked aggregate, claims 1 (in part)). CONNON teaches that the hydrogel can be appropriately packaged for transportation of cells, wherein the hydrogel can be enclosed within a water-tight or air-tight material or container such as within a vial or cryovial or tissue culture flask (Paragraph [0066] and [0068]). (interpreted as transporting, packaging, and sealing the multicellular aggregate-containing alginate hydrogel in water or air tight receptacle, claims 1 (in part)). CONNON teaches that the cells can be transported, wherein the second location is a location which is remote from the first location, e.g. at least 1 mile, or more than 5 miles, from the first location; and the hydrogels are stored during transportation can be stored at -80° C to 45° C (Paragraphs [0070]; and [0079]) (interpreted as transporting the packaged multicellular aggregate from first to second location; encompassing a temperature of 10 to 30 C; and a distance between the locations is at least 1 mile, claim 1 (in part)).
Connon does not specifically exemplify that the adjoining cells of the multicellular aggregate are in direct contact with each other by adhering to or touching each other (instant claim 1 (in part) and claim 21) and does not specifically exemplify a cell culture plate comprising a plurality of wells selected from 4-, 6-, 8-, 12-, 24-, 48-, 96-, 384-, or 1536-well cell culture plate (instant claim 11).
Regarding claim 1 (in part) and 21, King teaches that cell type of origin for ovarian cancers is still being determined, and thus, culturing normal cells will definitively determine the cell type of origin (Abstract). King teaches that this will allow for development of more accurate biomarkers, animal models with tissue-specific gene changes, and better prevention strategies (Abstract). King teaches that a method for the preparation, separation, and embedding of ovarian and oviductal organ pieces into alginate hydrogels, which can be maintained in culture for up to two weeks (Abstract) (interpreted as adjoining cells are in direct contact by being physically connect with each other, instant claim 1 (in part) and 21). King teaches that this method allows for the growth of ovarian surface epithelium (OSE) without genetic immortalization (Abstract). King teaches that the CaCl2 solution is used to help the crosslinking the alginate upon tissue encapsulation (pg. 1, protocol # 1). King teaches that the culture of these tissue types in alginate hydrogels provides mechanical support to maintain the three dimensional architecture of the tissue (pg. 4, Discussion, Paragraph 3).
Regarding claim 11, King teaches that the four alginate gels can be transferred into a single well of a 24 well plate (pg. 1, protocol # 1).
Therefore, in view of the benefits of determining the origin of ovarian cells for development of more accurate biomarkers, animal models with tissue-specific gene changes, and better prevention strategies as taught by King, it would have been prima facia obvious for one of ordinary skill in the art to modify the method of transporting live isolated cells (i.e. cells that are not in direct contact with each other) as disclosed by Connon with the ovarian and oviductal organ pieces that are encapsulated in the alginate hydrogel as taught by King with a reasonable expectation of success in transporting organs in an alginate hydrogel. It would have been prima facia obvious to combine the cited sources because Connon teaches a method of transporting live cells which are encapsulated in in alginate hydrogels, packed in a receptacle, and transported, and King teaches that ovarian and oviductal organ pieces are cultured in an alginate hydrogel, packed in a receptacle, and can be stored for up to 2 weeks, and teaches that the culture of these tissue types in alginate hydrogels provides mechanical support to maintain the three dimensional architecture of the tissue.
Regarding claim 2, Connon teaches that the cells are released at the second location (Paragraph [0015]). (interpreted as releasing the multicellular from the alginate hydrogel at the second location, claims 2). Connon teaches that the hydrogel with living cells retained therein can be stored (e.g., during transportation) for up to 10 to 20 weeks before being released from the hydrogels (paragraph [0082]).
Regarding claim 3, Connon teaches that methods (described supra) can fulfill an order or request for cells, which comprises receiving and order or request for cells (Paragraph [0018]) (interpreted as fulfilling an order or request for in vitro multicellular aggregate and receiving an order or request for a multicellular aggregate, claim 3).
Regarding claim 4, Connon teaches that the cells can be transported, wherein the second location is a location which is remote from the first location, e.g. at least 1 mile, or more than 5 miles, from the first location; (Paragraphs [0070]).
Regarding claim 5, Connon teaches that the hydrogel comprises a plurality of individual cells retained therein; and that the cells can be stored for up to 10 or 20 weeks according to the methods (described supra) (Paragraphs [0049]; and [0082]) (interpreted as storing a multicellular aggregate comprising a plurality of directly adjoining cells for at least 24 hours, claim 5).
Regarding claim 6, Connon teaches that the cells are released at the second location (Paragraph [0015]) (interpreted as releasing the multicellular from the alginate hydrogel at the second location, claims 6). Connon teaches that the hydrogel with living cells retained therein can be stored (e.g., during transportation) for up to 10 to 20 weeks before being released from the hydrogels (paragraph [0082]).
Regarding claims 9 and 10, Connon teaches that the hydrogel can be contained within a vial or tissue culture flask (interpreted as the receptacle is a sealed storage vial or a cell culture vessel, claims 9 and 10) (Paragraph [0068]).
Regarding claim 12, Connon teaches that the hydrogel-forming polymer is alginic acid or an alginate salt of a metal ion including lithium, sodium or potassium alginate; as well as, magnesium, calcium, barium or strontium alginate (Paragraph [0024]).
Regarding claim 13, Connon teaches that HCE and limbal epithelial cells were suspended in 0.3%, 0.6% and/or 1.2% (w/v) sodium alginate solutions before gelling into masses and discs using 102 mM CaC12 (interpreted as where the alginate is in an amount of alginate encompassing 0.5% w/v to 5.0% w/v sodium alginate, claim 12) (paragraph [0142]). Connon teaches a 0.6% calcium alginate hydrogel; as well as, 1.2% calcium alginate hydrogel comprising living cells (interpreted as where the alginate is in an amount of alginate encompasses 0.5% w/v to 5.0% w/v calcium alginate, claims 12 and 13) (Paragraphs [0073]-[0074]).
Regarding claim 14, Connon teaches that gel spheres are formed by dispensing alginate or alginate/HEC solutions into CaCl2 (interpreted as spheres, claim 14) (paragraph [0074], lines 1-2).
Regarding claim 15, Connon teaches that the cells that are a heterogenous mixture of stem cells and differentiated cells (interpreted as the multicellular aggregate comprises heterogenous cell types, claim 15) (Paragraph [0051], lines 1-3).
Regarding claim 16 and 17, Connon teaches the cells that are all of the same type, and preferably mammalian cells; and that the subject animal is a mammal, including a human (interpreted as the multicellular aggregate comprises homogenous cell types; and human cells, claims 16 and 17) (Paragraphs [0049]; and [0094]).
Regarding claim 18, Connon teaches the use of corneal fibroblasts (interpreted as hCSF, claim 18) (Paragraph [0051]).
Regarding claim 19 and 20, Connon teaches the gelling of the hydrogel by a multivalent metal cation, like calcium chloride (interpreted as polymerization is induced by a chemical agent, claims 19 and 20) (Paragraph [0044]).
Regarding claim 22, Connon and King appear to be silent as to the concentration of cells in the aggregate. However, per M.P.E.P. § 2144/05(11), 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCP A 1955). Since the instant specification is not appear to support the notion that concentration of cells in the multicellular aggregate is not critical, the number of cells recited in claim 22 is not considered to support patentability.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103 as obvious over the art.
Response to Arguments as they apply to rejection of claims 1-6 and 9 -22 under 35 USC § 103
Applicant’s arguments filed 9 June, 2025 have been fully considered but they are not persuasive. Applicant essentially asserts (a) Claim 1 has been amended (Remarks, pg. 10, first paragraph); (b) King does not teach multicellular aggregates that can be encapsulated in a sealed receptacle to remain viable during storage (Remarks, pg. 8, last paragraph), (c) it is surprising and unexpected that the inventors found that multicellular aggregates are viable after being kept in a sealed receptacle, as required by the claims (Remarks, pg. 9, last paragraph).
Regarding (a), it is not clear whether and how the claim has been amended. Please clarify how claim 1 has been amended.
Regarding (b), Applicant’s arguments that King does not teach multicellular aggregates that can be encapsulated in a sealed receptacle to remain viable during storage is not found persuasive. Applicant notes that Connon teaches that the individually encapsulated cells maintain cell viability in a sealed receptacle, while King teaches the culturing of an organoid in an unsealed receptable. Moreover, the instant claims require “iii) packaging and sealing the reversibly cross-linked multicellular aggregate containing alginate hydrogel in a water tight or air tight receptacle to provide a packaged in vitro multicellular aggregate”, but the instant claims are not so limited such that this is the only possible steps for producing a perfusable engineered vasculature. The claims are "open" and thus lend themselves to additional culturing of the cell with an alginate hydrogel-forming polymer gel under or other conditions corresponding to the in-situ conditions. Furthermore, Applicant is reminded that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant’s assertion that King does not teach multicellular aggregates that can be encapsulated in a sealed receptacle to remain viable during storage is not found persuasive. As an initial matter, Applicant is reminded that the rejection of record is based on the combination of Connon and King, wherein Connon teaches a method of transporting individually encapsulated cells which are encapsulated in in alginate hydrogels, packed in a receptacle, and transported, and King teaches that ovarian and oviductal organ pieces are cultured in an alginate hydrogel, packed in a receptacle, and can be stored for up to 2 weeks. Thus, it would have been prima facia obvious for one of ordinary skill in the art to modify the method of transporting live isolated cells (i.e. cells that are not in direct contact with each other) as disclosed by Connon with the ovarian and oviductal organ pieces that are encapsulated in the alginate hydrogel as taught by King to produce in vitro multicellular aggregate for transportation.
Further, Applicant notes that King teaches, in Figure 1H, that “alginate encapsulated organoids incubated in culture medium are cultured in an unsealed receptacle (24 well plate), thus allowing essential gaseous exchange” (Remarks, pg. 9, first paragraph). The instantly claim 1 recites the following steps: “(i) contacting the invitro multicellular aggregate with an alginate hydrogel forming polymer, (ii) polymerizing the alginate hydrogel-forming polymer to form a reversibly cross-linked multicellular aggregate-containing alginate hydrogel, and (iii) packaging and sealing the reversibly cross-linked multicellular aggregate in a airtight receptacle.” The instantly recited claim does not require that culturing the multicellular aggregate has to be done in a sealed receptacle.
Further, the as-Filed Specification teaches that the entrapped or encapsulated cellular material can be packaged in a sealed receptacle for effective storage or delivery to its point of use (Paragraph [0007]). The as-Filed Specification teaches that the sealed storage vial can be a 24 well cell culture plate (Paragraph [0047] – [0050]). The as-Filed Specification teaches prior to storage, culture medium was removed and replaced with 300 μL culture medium (− Hydrogel) or 300 μL calcium alginate hydrogel composite (+ Hydrogel) before sealing plates and storing at 15° C (Paragraph [0230]). King teaches that the CaCl2 solution is used to help the crosslinking the alginate upon tissue encapsulation (pg. 1, protocol # 1). Thus, one of ordinary skill in the art, using the teachings of Connon and King, would be able to culture the multicellular aggregate in a cultured in an alginate hydrogel in an unsealed receptacle (24 well plate), culture the multicellular aggregate in the calcium alginate hydrogel composite, and then seal the receptacle for transportation and viability.
Regarding (c), Applicant notes that it is surprising and unexpected that the inventors found that multicellular aggregates are viable after being kept in a sealed receptacle, however this argument is not found persuasive. The as-Filed Specification teaches that the inventors have surprisingly shown that the entrapment or encapsulation of a multicellular aggregate in a reversibly cross-linked hydrogel protects the cellular material in the aggregate from the mechanical and environmental stresses of storage and/or transportation (Paragraph [0007]). Thus, the surprising results are actually the use of the encapsulation of a multicellular aggregate, not that the multicellular aggregates are viable after being kept in a sealed receptacle. Applicant notes examples 1 and 2, however, these examples are not convincing of the unexpected result that the multicellular aggregates are viable after being kept in a sealed receptacle. Specifically, in example 2, Applicant teaches that the viability and integrity of ASC monolayers was maintained with alginate hydrogel protection (Paragraph [0230]).
Thus, the rejected is maintained for the reasons of record.
Conclusion
Claims 1 – 6 and 9 - 22 remain rejected.
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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VYOMA SHUBHAM TIWARI whose telephone number is (571)272-2954. The examiner can normally be reached M-F 8:30 - 5:30 EST.
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/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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