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 .
Election/Restrictions
Regarding claim 26, the elected species is: poly(glycerol sebacate) and poly(octamethylene maleate (anhydride) citrate) (POMaC).
Specification
The disclosure is objected to because of the following informalities:
Regarding the specification, in paragraphs [0046], [0166], and [00169], the term “overtime” is recited in total four times. This term should be written as “over time”.
Appropriate correction is required.
Claim Objections
The previous claim objections are withdrawn in light of the amendments.
Claims 21 and 45 are objected to because of the following informalities:
Regarding claim 21, in line 9, the term “as heathy native skeletal muscle” should be “as healthy native skeletal muscle”.
Regarding claim 21, in line 18, the term “the sensing elements” should be “the at least two elastic sensing elements”.
Regarding claim 44, the claimed limitation is already present in claim 21.
Regarding claim 45, in line 3, the term “comprising” should be “further comprises”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The previous 35 U.S.C. § 112(a) rejections are withdrawn in light of the Applicant Remarks.
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 21-32, 41, and 44-45 are rejected under 35 U.S.C. 103 as being unpatentable over Miklas (US 20160282338) (previously cited) in view of Bashir (US 10906169) (previously cited), further in view of evidentiary reference Betts (“10.2: Skeletal Muscle”) (previously cited).
Regarding claim 21, Miklas discloses a tissue system comprising a three-dimensional ex vivo skeletal muscle tissue (paragraphs [0173] for hydrogel; and for skeletal muscle cells [0177]) and a bioreactor (paragraph [0012]), wherein the three-dimensional ex vivo skeletal muscle tissue comprises a hydrogel (paragraph [0173]) mixture and a plurality of cells that includes skeletal muscle cells (paragraph [0177]), wherein at least a portion of the cells are encapsulated inside the hydrogel (paragraph [0173]), wherein the skeletal muscle tissue is characterized by one or more contractions in response to an electrical and/or chemical stimulation (see inherency argument 1, below for this property of skeletal muscle tissue), and the skeletal muscle tissue does not contract in the absence of electrical and/or chemical stimulation (see inherency argument 2, below for this property of skeletal muscle tissue), wherein the skeletal muscle tissue (paragraph [0177]) comprises an A band, an I band, a Z line, [an] M line, and an H zone (these elements are inherent to skeletal muscle tissue, see Betts (“10.2: Skeletal Muscle”) (previously cited) in Figs. 10.4 “Muscle Fiber” and 10.5 “The Sarcomere”), and has substantially the same structural organization as [healthy] native muscle tissue (paragraphs [0645]-[0647] “stimulated samples displayed a sarcomeric organization more compatible with mature cells than non-stimulated controls”), and wherein the bioreactor (paragraph [0012]) comprises:
a device having a well (paragraph [0019]) configured for growing the three-dimensional ex vivo skeletal muscle tissue from the cells seeded therein (paragraphs [0019] and [0177]), wherein the well has a bottom (paragraph [0095], Fig. 37(a), hot embossing PMMA base); and
at least two elastic sensing elements (paragraphs [0095], [0103]-[0105], and [0773]; Fig. 37(d), polymer wires affixed thereon) disposed across the well (paragraph [0095], Fig. 37(d)) such that there is a gap between the at least two elastic sensing elements and the bottom of the well (paragraph [0093], Fig. 35; and paragraph [0021]), wherein the at least two elastic sensing elements are configured to: (a) permit attachment of the three-dimensional ex vivo skeletal muscle tissue formed there between, thereby suspending the three-dimensional ex vivo skeletal muscle tissue above the bottom of the well (paragraphs [0021] and [0024]), and (b) deform in response to a contractile force exerted on the sensing elements by the three-dimensional (paragraph [0022]) ex vivo skeletal muscle tissue (paragraphs [0173] and [0177]),
wherein the three-dimensional ex vivo skeletal muscle tissue is produced using a stimulation protocol comprising a plurality of pulses, wherein each pulse is at least about 1 Hz to 6 Hz applied for a duration of at least about one millisecond (paragraph [0596]).
Miklas does not disclose:
a hydrogel mixture comprising thrombin
a plurality of pulses separated by no electrical stimulations, wherein each pulse is at least about 10 Hz applied for a duration of at least about one second
Regarding feature 1, Bashir discloses:
a hydrogel mixture comprising thrombin (col. 18, lines 8-31).
In the analogous art of muscle-powered biological machines, it would have been obvious to one skilled in the art before the effective filing date to modify Miklas with the thrombin of Bashir in order to cross-link the hydrogel comprising skeletal muscle cells into a stable 3D gel network and compaction of the muscle tissue (Bashir, col. 28, lines 34-37 and col. 49, lines 10-15).
Regarding inherency argument 1, the limitation “the skeletal muscle tissue is characterized by one or more contractions in response to an electrical and/or chemical stimulation”, this property is an inherent property to skeletal muscle tissue, as skeletal muscles contract in response to an electrical and/or chemical stimulation from the nervous system (see pgs. 7-10 of 10 of Betts (“10.2: Skeletal Muscle”) (previously cited)). Neurons acquire their ability to electrically signal from the ions present (or not present), so the Examiner also considers the electrical stimulation a chemical stimulation. Regarding the limitation “and/or chemical stimulation”, this limitation is claimed in the alternative, so no further rejections are needed at this time. Additionally, the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Miklas would be fully capable of operating in this manner given the hydrogel and the skeletal muscle tissue.
Regarding inherency argument 2, the limitation “wherein the three-dimensional ex vivo skeletal muscle tissue does not contract in the absence of electrical and/or chemical stimulation”, skeletal muscle cells do not have the inherent ability to contract on their own (see pg. 7 of 10 of Betts (“10.2: Skeletal Muscle”) (previously cited)), and require a stimulus (such as an electrical and/or chemical stimulation of independent claim 21, such as a movement of ions across a membrane, usually due to efferent neuronal firing within the human body) (see pg. 7 of 10 of Betts (“10.2: Skeletal Muscle”) (previously cited)). Additionally, the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Miklas would be fully capable of operating in this manner given the hydrogel and the skeletal muscle tissue.
Regarding feature “substantially the same structural organization as [healthy] native skeletal muscle tissue”, Miklas has shown that electrically stimulated samples displayed a sarcomeric organization more compatible with mature cells than non-stimulated controls as shown by a significantly higher presence of H-zones per sarcomere (Miklas, paragraph [0647]). It would have been obvious (if not already deemed inherent to Miklas’s invention) to one skilled in the art before the effective filing date to modify the modified device of Miklas with skeletal muscle tissue in order to obtain skeletal muscle tissue with substantially the same structural organization as healthy native skeletal muscle tissue to obtain skeletal muscle for transplantation, for example. Also see MPEP § 2113 (Product-by-Process Claims), below.
Regarding feature 2, the feature is an intended use or manner of operating the invention. Regarding the limitation, the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Miklas would be fully capable of operating in this manner given the structure of the bioreactor, skeletal muscle tissue, a well, hydrogel, and at least two elastic sensing elements of Miklas. Also see MPEP § 2113 (Product-by-Process Claims), below.
Regarding product-by-process limitations: “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” MPEP § 2113.
Regarding claim 22, Miklas discloses at least two electrodes configured to apply an electrical stimulation (paragraphs [0020] and [0278]) to the three-dimensional ex vivo skeletal muscle tissue (paragraphs [0173] for hydrogel; and for skeletal muscle cells [0177]) of the bioreactor (paragraph [0012]).
Regarding claim 23, Miklas discloses wherein the at least two elastic sensing elements (paragraphs [0095], [0103]-[0105], and [0773]; Fig. 37(d), polymer wires affixed thereon) comprise a synthetic polymer (paragraph [0186]), a biologic polymer (paragraph [0186]), or a combination thereof (paragraph [0189]).
Regarding claim 24, Miklas discloses wherein the polymer is degradable (paragraph [0186]).
Regarding claim 25, Miklas discloses wherein the polymer is nondegradable (paragraph [0186]).
Regarding claim 26, Miklas discloses wherein each elastic sensing element comprises (paragraphs [0095], [0103]-[0105], and [0773]; Fig. 37(d), polymer wires affixed thereon) a polymer selected from the elected species: poly(glycerol sebacate) (paragraph [0228]) and poly(octamethylene maleate (anhydride) citrate) (POMaC) (paragraph [0227]).
Regarding the remainder of the claim, the remainder was not elected.
Regarding claim 27, Miklas discloses the polymer comprises POMaC (paragraph [0227]).
Regarding claim 28, Miklas discloses wherein the at least two elastic sensing elements (paragraphs [0095], [0103]-[0105], and [0773]; Fig. 37(d), polymer wires affixed thereon) have an elasticity somewhere within the range of 20 kPa to 0.5 MPa (paragraphs [0773]-[0775] and Figs. 45-47).
Miklas does not disclose the exact data and endpoints of the ranges in each experiment within its PGPub, as it only states “The elastic modulus … fall[s] right into the range of adult myocardium” (Miklas, paragraph [0773]), wherein the human myocardium was previously stated as being “from about 20 kPa to 0.5 MPa” (Miklas, paragraph [0773]).
However, because the above elasticity’s range is within the range of human myocardium according to Miklas, it is also within the claimed range of 10 kPa to 0.8 MPa; therefore, Miklas reads on the claimed limitation.
Regarding claim 29, Miklas discloses wherein the at least two elastic sensing elements (paragraphs [0095], [0103]-[0105], and [0773]; Fig. 37(d), polymer wires affixed thereon) are in the form of polymer wires (paragraph [0092] and [0773]).
Regarding claim 30, Miklas discloses wherein the bioreactor comprises 2 to 25 elastic sensing elements per well (paragraphs [0735]-[0736] “2 wires” or claim 88 “from 2 to 25”).
Regarding claim 31, Miklas discloses wherein the bioreactor comprises a multi-well plate (paragraphs [0736]-[0742] and Figs. 37a-d3 and 38a-c).
Regarding claim 32, Miklas discloses wherein the multi-well plate comprises
6 wells (paragraph [0737]), 12 wells (paragraph [0737]), 24 wells (paragraph [0737]), 96 wells (paragraphs [0737] and [0741]), 384 wells (paragraph [0737]), or 1536 wells (paragraph [0041]).
Regarding the remainder of the claim, “8 wells”, this limitation is claimed in the alternative; no further rejections are required at this time.
Regarding claim 41, Miklas discloses wherein the plurality of cells further comprises fibroblasts (paragraphs [0504] and [0512]; claim 98).
Regarding claim 44, Miklas discloses a plurality of pulses (paragraphs [0595]-[0597] and [0608]).
Miklas does not disclose wherein each pulse is at least about 10 Hz applied for a duration of about one second.
Regarding the limitation, the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Miklas would be fully capable of operating in this manner given the hydrogel and the skeletal muscle tissue. Also see MPEP § 2113 (Product-by-Process Claims).
Regarding claim 45, Miklas discloses wherein the stimulation protocol [comprises] a ramp rate (paragraphs [0596]-[0597]).
Miklas does not disclose wherein the stimulation protocol [comprises] applying a first frequency for a first duration and a second frequency for a second duration, wherein the first frequency is increased to the second frequency at a ramp rate which is at least about 0.1 Hz/hour.
Regarding the limitation, the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Miklas would be fully capable of operating in this manner given the hydrogel and the skeletal muscle tissue. Also see MPEP § 2113 (Product-by-Process Claims).
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Miklas (US 20160282338) (previously cited) in view of Bashir (US 10906169) (previously cited) and evidentiary reference Betts (“10.2: Skeletal Muscle”) (previously cited) as applied to claim 41, further in view of Lancaster (US 20210290823) (previously cited).
Regarding claim 42, Miklas does not disclose wherein the fibroblasts and the skeletal muscle tissue are at a ratio of between about 1:5 and 1:50.
Lancaster discloses wherein the fibroblasts and the skeletal muscle tissue are at a ratio of between about 1:5 and 1:50 (paragraph [0008]).
In the analogous art of muscle cell patches, it would have been obvious to one skilled in the art before the effective filing date to modify modified Miklas with the ratio of fibroblasts and skeletal muscle tissue of Lancaster in order to provide a scaffold that is capable of spontaneous synchronized contractions across the surface of the scaffold (Lancaster, paragraph [0008]). Additionally, the contractile construct can be implanted in a subject in need thereof after culturing. The construct may be implanted prior to onset of cellular contraction and/or patch level contraction (Lancaster, paragraph [0007]).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The double patenting rejections under commonly assigned 17798047 (Radisic) (previously cited) are withdrawn, as Radisic is now abandoned as of 03/14/2026.
Claims 21-22, 41, and 44-45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of U.S. Patent No. 12595449 (Aschar-Sobbi) (newly cited) in view of Bashir (US 10906169) (previously cited), further in view of evidentiary reference Betts (“10.2: Skeletal Muscle”) (previously cited).
Regarding claim 21, Aschar-Sobbi discloses a tissue system (claim 1) comprising a three-dimensional (claim 1) ex vivo skeletal muscle tissue (claims 1 and 13) and a bioreactor (claim 1), wherein the three-dimensional (claim 1) ex vivo skeletal muscle tissue (claims 1 and 13) comprises a hydrogel (claim 13) and a plurality of cells that includes skeletal muscle cells (claim 13), wherein at least a portion of the cells are encapsulated inside the hydrogel (claim 13), wherein the skeletal muscle tissue (claims 1 and 13) is characterized by one or more contractions in response to an electrical stimulation (claim 1; and see inherency argument 1, below) and the skeletal muscle tissue does not contract in the absence of electrical and/or chemical stimulation (see inherency argument 2, below) and wherein the bioreactor comprises:
a device having a well (claim 1) configured for growing the three-dimensional (claim 1) ex vivo skeletal muscle tissue (claims 1 and 13) from the cells seeded therein (claim 1), wherein the well has a bottom (claim 1); and
at least two elastic sensing elements (claim 1) disposed across the well such that there is a gap between the at least two elastic sensing elements and the bottom of the well (claim 1), wherein the at least two elastic sensing elements are configured to: (a) permit attachment of the three-dimensional ex vivo skeletal muscle tissue (claims 1 and 13) formed there between, thereby suspending the three-dimensional ex vivo skeletal muscle tissue (claims 1 and 13) above the bottom of the well (claim 1), and (b) deform in response to a contractile force exerted on the sensing elements (claim 1) by the three-dimensional ex vivo skeletal muscle tissue (claims 1 and 13).
Aschar-Sobbi does not disclose in the claims:
a hydrogel mixture comprising thrombin.
Regarding feature 1, Bashir discloses:
a hydrogel mixture comprising thrombin (col. 18, lines 8-31).
In the analogous art of muscle-powered biological machines, it would have been obvious to one skilled in the art before the effective filing date to modify Aschar-Sobbi with the thrombin of Bashir in order to cross-link the hydrogel comprising skeletal muscle cells into a stable 3D gel network and compaction of the muscle tissue (Bashir, col. 28, lines 34-37 and col. 49, lines 10-15).
Regarding inherency argument 1, the limitation “the skeletal muscle tissue is characterized by one or more contractions in response to an electrical and/or chemical stimulation”, this property is an inherent property to skeletal muscle tissue, as skeletal muscles contract in response to an electrical and/or chemical stimulation from the nervous system (see pgs. 7-10 of 10 of Betts “10.2: Skeletal Muscle”). Neurons acquire their ability to electrically signal from the ions present (or not present), so the Examiner also considers the electrical stimulation a chemical stimulation. Regarding the limitation “and/or chemical stimulation”, this limitation is claimed in the alternative, so no further rejections are needed at this time. Additionally, the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Aschar-Sobbi would be fully capable of operating in this manner given the hydrogel and the skeletal muscle tissue.
Regarding inherency argument 2, the limitation “wherein the three-dimensional ex vivo skeletal muscle tissue does not contract in the absence of electrical and/or chemical stimulation”, skeletal muscle cells do not have the inherent ability to contract on their own (see pg. 7 of 10 of Betts “10.2: Skeletal Muscle”), and require a stimulus (such as an electrical and/or chemical stimulation of independent claim 21, such as a movement of ions across a membrane, usually due to efferent neuronal firing within the human body) (see pg. 7 of 10 of Betts “10.2: Skeletal Muscle”). Additionally, the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Aschar-Sobbi would be fully capable of operating in this manner given the hydrogel and the skeletal muscle tissue.
Regarding claim 22, Aschar-Sobbi discloses wherein the bioreactor further comprises at least two electrodes (claim 1) configured to apply an electrical stimulation (claim 1) to the three-dimensional ex vivo skeletal muscle tissue (claims 1 and 13) of the bioreactor (claim 1).
Regarding claim 41, Aschar-Sobbi discloses wherein the plurality of cells further comprises fibroblasts (claim 13).
Regarding claim 44, Aschar-Sobbi discloses wherein the three-dimensional ex vivo skeletal muscle tissue is produced using a stimulation protocol (claim 1).
Aschar-Sobbi does not disclose wherein the three-dimensional ex vivo skeletal muscle tissue is produced using a stimulation protocol comprising a plurality of pulses separated by no electrical stimulations, wherein each pulse is at least about 10 Hz applied for a duration of about one second.
Regarding the limitation, the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Aschar-Sobbi would be fully capable of operating in this manner given the hydrogel and the skeletal muscle tissue. Also see MPEP § 2113 (Product-by-Process Claims).
Regarding claim 45, Aschar-Sobbi discloses the three-dimensional ex vivo skeletal muscle tissue is produced using a stimulation protocol (claim 1).
Aschar-Sobbi does not disclose the three-dimensional ex vivo skeletal muscle tissue is produced using a stimulation protocol comprising applying a first frequency for a first duration and a second frequency for a second duration, wherein the first frequency is increased to the second frequency at a ramp rate which is at least about 0.1 Hz/hour.
Regarding the limitation, the manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Aschar-Sobbi would be fully capable of operating in this manner given the hydrogel and the skeletal muscle tissue. Also see MPEP § 2113 (Product-by-Process Claims).
Claim 23 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 13 of U.S. Patent No. 12595449 (Aschar-Sobbi) (newly cited) in view of Bashir (US 10906169) (previously cited) as applied to claim 21, further in view of evidentiary reference Betts (“10.2: Skeletal Muscle”) (previously cited).
Regarding claim 23, Aschar-Sobbi discloses wherein the at least two sensing elements comprise a synthetic polymer (claim 7), a biologic polymer (claim 7), or a combination thereof (claim 7).
In the analogous art of 3D tissue culture, it would have been obvious to one skilled in the art before the effective filing date to modify the 3D tissue culture system of Aschar-Sobbi with the polymer of claim 7 in order to produce a sensing element that is capable of deforming in response to a contractile force exerted on the sensing elements by the three-dimensional tissue (Aschar-Sobbi, claim 1).
Claim 24 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 13 of U.S. Patent No. 12595449 (Aschar-Sobbi) (newly cited) in view of Bashir (US 10906169) (previously cited) as applied to claim 23, further in view of evidentiary references Miklas (US 20160282338) (previously cited) and Betts (“10.2: Skeletal Muscle”) (previously cited).
Regarding claim 24, Aschar-Sobbi discloses wherein the sensing elements comprise a synthetic polymer (claim 7), a biologic polymer (claim 7), or a combination thereof (claim 7).
Aschar-Sobbi does not disclose wherein the polymer is degradable.
Evidentiary reference Miklas discloses wherein the polymer is degradable (paragraph [0176] “POMaC” is biodegradable).
Claim 25 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 13 of U.S. Patent No. 12595449 (Aschar-Sobbi) in view of Bashir (US 10906169) as applied to claim 23, further in view of Miklas (US 20160282338) and evidentiary reference Betts (“10.2: Skeletal Muscle”).
Regarding claim 25, Aschar-Sobbi does not disclose wherein the polymer is nondegradable.
Miklas discloses wherein the polymer is nondegradable (paragraph [0186]).
In the analogous art of 3D tissue culture, it would have been obvious to one skilled in the art before the effective filing date to modify the polymer of modified Aschar-Sobbi to be nondegradable as in Miklas in order to not have the polymer scaffold break down over time during the cell culture.
Claims 26-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7-8, and 13 of U.S. Patent No. 12595449 (Aschar-Sobbi) (newly cited) in view of Bashir (US 10906169) (previously cited) as applied to claim 21, further in view of evidentiary reference Betts (“10.2: Skeletal Muscle”) (previously cited).
Regarding claim 26, Aschar-Sobbi discloses wherein each elastic sensing element comprises a polymer selected from the group consisting of: poly(glycerol sebacate) (claim 7) and poly(octamethylene maleate (anhydride) citrate) (POMaC) (claims 7-8).
In the analogous art of 3D tissue culture, it would have been obvious to one skilled in the art before the effective filing date to modify the 3D tissue culture system of Aschar-Sobbi with the polymers of claims 7 and/or 8 in order to produce a sensing element that is capable of deforming in response to a contractile force exerted on the sensing elements by the three-dimensional tissue (Aschar-Sobbi, claim 1).
Regarding the remainder of the claim, the remainder was not elected (see election of species).
Regarding claim 27, Aschar-Sobbi discloses wherein the polymer comprises POMaC (claims 7 and 8).
In the analogous art of 3D tissue culture, it would have been obvious to one skilled in the art before the effective filing date to modify the 3D tissue culture system of Aschar-Sobbi with the polymers of claims 7 and/or 8 in order to produce a sensing element that is capable of deforming in response to a contractile force exerted on the sensing elements by the three-dimensional tissue (Aschar-Sobbi, claim 1).
Claims 28-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, and 13 of U.S. Patent No. 12595449 (Aschar-Sobbi) (newly cited) in view of Bashir (US 10906169) (previously cited) as applied to claim 21, further in view of evidentiary reference Betts (“10.2: Skeletal Muscle”) (previously cited).
Regarding claim 28, Aschar-Sobbi discloses wherein the at least two elastic sensing elements have an elasticity from about 20 kPa to 0.5 MPa (claim 10). This range is within the claimed range of 10 kPa to 0.8 MPa, so Aschar-Sobbi renders this limitation rejected.
In the analogous art of 3D tissue culture, it would have been obvious to one skilled in the art before the effective filing date to modify the 3D tissue culture system of Aschar-Sobbi with the sensing elements of claim 10 in order to produce a sensing element that is capable of deforming in response to a contractile force exerted on the sensing elements by the three-dimensional tissue (Aschar-Sobbi, claim 1).
Regarding claim 29, Aschar-Sobbi discloses wherein the at least two elastic sensing elements are in the form of polymer wires (claim 10).
In the analogous art of 3D tissue culture, it would have been obvious to one skilled in the art before the effective filing date to modify the 3D tissue culture system of Aschar-Sobbi with the polymer wire sensing elements of claim 10 in order to produce a sensing element that is capable of deforming in response to a contractile force exerted on the sensing elements by the three-dimensional tissue (Aschar-Sobbi, claim 1).
Claims 30-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, and 13 of U.S. Patent No. 12595449 (Aschar-Sobbi) (newly cited) in view of Bashir (US 10906169) (previously cited) as applied to claim 21, further in view of evidentiary reference Betts (“10.2: Skeletal Muscle”) (previously cited).
Regarding claim 30, Aschar-Sobbi discloses wherein the bioreactor comprises 2 to 25 elastic sensing elements per well (claim 7).
In the analogous art of three-dimensional tissue culture, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of modified Aschar-Sobbi with the 2 to 25 sensing elements per well in order to sense contraction on the at least two elastic sensing elements to simulate a physiological environment that is native to the tissue and/or permit measurement of the contractile force (Aschar-Sobbi, claim 1).
Regarding claim 31, Aschar-Sobbi discloses wherein the bioreactor comprises a multi-well plate (claim 7).
In the analogous art of three-dimensional tissue culture, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of modified Aschar-Sobbi with the multi-well plate in order to have multiple wells in order to parallelize and perform a plurality of tissue cultures under varying electrical and/or chemical conditions if needed.
Regarding claim 32, Aschar-Sobbi discloses wherein the multi-well plate comprises 6 wells, 12 wells, 24 wells, or 96 wells (claim 7).
In the analogous art of three-dimensional tissue culture, it would have been obvious to one skilled in the art before the effective filing date to modify the bioreactor of modified Aschar-Sobbi with the multi-well plate in order to have multiple wells in order to parallelize and perform a plurality of tissue cultures under varying electrical and/or chemical conditions if needed.
Regarding the limitation “8 wells, … 384 wells, or 1536 wells”, this limitation is claimed in the alternative. No further rejections are required at this time.
Claim 42 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of U.S. Patent No. 12595449 (Aschar-Sobbi) (newly cited) in view of Bashir (US 10906169) (previously cited) as applied to claim 41, further in view of Lancaster (US 20210290823) (previously cited) and evidentiary reference Betts (“10.2: Skeletal Muscle”) (previously cited).
Regarding claim 42, Aschar-Sobbi does not disclose wherein the fibroblasts and the skeletal muscle tissue are at a ratio of between about 1:5 and 1:50.
Lancaster discloses wherein the fibroblasts and the skeletal muscle tissue are at a ratio of between about 1:5 and 1:50 (paragraph [0008]).
In the analogous art of muscle cell patches, it would have been obvious to one skilled in the art before the effective filing date to modify modified Radisic with the ratio of fibroblasts and skeletal muscle tissue of Lancaster in order to provide a scaffold that is capable of spontaneous synchronized contractions across the surface of the scaffold (Lancaster, paragraph [0008]). Additionally, the contractile construct can be implanted in a subject in need thereof after culturing. The construct may be implanted prior to onset of cellular contraction and/or patch level contraction (Lancaster, paragraph [0007]).
Additional Prior Art References
The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure.
Parker (US 20140342394) (newly cited) – This invention is a muscle chip and method of use thereof.
Response to Arguments
Applicant’s arguments filed 04/10/2026 have been fully considered, but they are not persuasive.
Regarding pg. 6 of 17 of Applicant remarks, regarding the amendments to the claims, amended claim 21 is examined. Amended claim 21 recites the limitation “wherein the skeletal muscle tissue comprises an A band, an I band, a Z line, [an] M line, and an H zone, and has substantially the same structural organization as [healthy] native skeletal muscle tissue”. However, the claim recites elements to the ex vivo skeletal muscle tissue are that are inherent to skeletal muscle tissue already, see evidentiary reference Betts (“10.2: Skeletal Muscle”), pgs. 4 and 6 of 10, under Figs. 10.4 and 10.5, respectively. Nevertheless, the amendment has written description support in paragraphs [0016] and [0071] of the specification.
Regarding pg. 6 of 17 of Applicant remarks, the phrase “the at least two elastic sensing elements” has been amended into claim 21. The examiner acknowledges this amendment.
Regarding pg. 6 of 17 of Applicant remarks, the last amendment “wherein the three-dimensional ex vivo skeletal muscle tissue is produced using a stimulation protocol comprising a plurality of pulses separated by no electrical stimulations, wherein each pulse is at least about 10 Hz applied for a duration of at least about one second”. The amendment is examined, see above. Written description for this amendment can be found in paragraphs [0110]-[0112].
Regarding pg. 7 of 17 of Applicant remarks, the previous claim objection is moot in light of the amendment; however, amended claim 21 is now objected to for a misspelled word.
Regarding pg. 7 of 17 of Applicant remarks, regarding the previous 35 U.S.C. § 112(a) rejections, these rejections are withdrawn. The Applicant has persuasively recited relevant portions of the specification (instant specification, paragraphs [0167]-[0169]) regarding the subject matter that was previously rejected under 35 U.S.C. § 112(a).
Regarding pg. 8 of 17 of Applicant remarks, the Declaration under 37 C.F.R. § 1.132 has been received. Additionally, the arguments for sustaining a 35 U.S.C. § 103 rejection are given below.
Regarding pg. 9 of 17 of Applicant remarks, claim 21, as amended, uses a stimulation protocol on ex vivo skeletal muscle tissue. As stated above, skeletal muscle tissue inherently comprises the features of an A band, an I band, a Z line, an M line, and an H zone, according to the evidentiary reference Betts (“10.2: Skeletal Muscle Tissue”).
Regarding pg. 10 of 17 of Applicant remarks, claim 21, as amended, uses the stimulation protocol comprising a plurality of pulses separated by no electrical stimulations, wherein each pulse is at least about 10 Hz applied for a duration of at least about one second. However, this stimulation protocol is an intended use or manner of operating the bioreactor. Furthermore, the structure purportedly imparted by the invention (the elements of the skeletal muscle recited in the claim 21) are already inherent to skeletal muscle tissue. As Miklas already discloses using skeletal muscle cells (Miklas, paragraphs [0177], [0499], [0504], [0534], [0834], and [0911]; and, claim 98) and as shown above, the structure to skeletal muscle tissue is inherent in the prior art invention.
Regarding pg. 10 of 17 of Applicant remarks, Miklas not only describes cardiomyocytes, but also skeletal muscle cells, as shown above. Although higher frequency stimulation protocols are not present in Miklas (to the degree claimed at 10 Hz or more), 3 Hz and 6 Hz are present. Not only would it have been obvious to one skilled in the art before the effective filing date to modify the modified Miklas device with the frequencies claimed as a matter of routine optimization because the frequency is a result-effective variable. The motivation for optimizing this result-effective variable is to stimulate cells to form well-defined alignment under a high frequency regimen to mature the tissue, such as with organized sarcomeric banding with converging myofibrils, numerous mitochondria, and desmosomes (Miklas, paragraphs [0646]-[0647]). MPEP § 2144.05(II). Additionally, the frequency of the apparatus is a matter of intended use or manner of operation of the apparatus. The manner of operating or intended use of a claimed apparatus does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Miklas would be fully capable of operating in this manner given the hydrogel and the skeletal muscle tissue. Also see MPEP § 2113 (Product-by-Process Claims).
Regarding pgs. 10-11 of 17 of Applicant remarks, Bashir is used to describe a hydrogel mixture comprising thrombin (col. 18, lines 8-31). Bashir is analogous art, as described above in the rejection. The remainder of the Bashir disclosure is not used in the rejection.
Regarding pg. 11-12 of 17 of Applicant remarks, a superior active tension force is allegedly produced compared to the tissues disclosed in the cited prior art, namely secondary reference Bashir. Even though a tissue with a different force may allegedly be formed due to the instant stimulation protocol, this is not commensurate in scope with the claims. The claims do not require a resulting tissue that has a specific tension force.
Regarding pg. 12 of 17 of Applicant remarks, although Miklas does not disclose the exact frequency of 10 Hz claimed, the Miklas invention still provides evidence that stimulating the tissues results in strengthening and maturation of muscle cells, see above arguments.
Regarding pg. 12 of 17 of Applicant remarks, Betts, an evidentiary reference, discloses the inherent structure of skeletal muscle tissue elements as claimed in amended claim 21 and rebutted in the arguments above.
Regarding pg. 12 of 17 of Applicant remarks, Lancaster discloses wherein the fibroblasts and the skeletal muscle tissue are at a ratio of between about 1:5 and 1:50 (paragraph [0008]).
Regarding pg. 12 of 17 of Applicant remarks, in response to the declaration, please see below arguments for reasons why the declaration is unpersuasive.
Regarding pg. 15 of 17 of Applicant remarks, application 17798047 (Radisic) has been abandoned. Therefore, these rejections are withdrawn.
Regarding pgs. 15-16 of 17 of Applicant remarks, about patent application 17798048 (Aschar-Sobbi), the application has been granted as U.S. Patent 12595449 (Aschar-Sobbi) as described in the Applicant remarks. However, the double patenting rejection is updated and sustained as shown above.
Regarding pg. 16 of 17 of Applicant remarks, claim 1 of Aschar-Sobbi (US 12595449), above, is directed to:
A system comprising:
two or more devices, wherein each device comprises:
a substrate; at least one pair of electrodes embedded at least partially in the substrate, the pair of electrodes having a first electrode and a second electrode separated by a gap;
at least one well having a bottom on the substrate, a first end in contact with the first electrode, and a second end in contact with the second electrode, the well configured for growing a tissue from cells seeded therein, wherein the pair of electrodes is configured to apply an electrical stimulation to the tissue; and
at least two elastic sensing elements disposed across the well such that there is a gap between the sensing elements and the bottom of the well, wherein the sensing elements are configured to: (a) permit attachment of the tissue formed therebetween, thereby suspending the tissue above the bottom of the well, and (b) deform in response to a contractile force exerted on the sensing elements by the tissue, thereby simulating a physiological environment that is native to the tissue and/or permitting measurement of the contractile force; and
a stimulator having two or more driver boards, wherein each driver board is configured to apply an electrical stimulation between each pair of electrodes of each device, thereby permitting the stimulator to independently control the application of the electrical stimulation between each pair of electrodes.
Additionally, claim 13 of Aschar-Sobbi (US 12595449) further defines the system of claim 1 by characterizing the cells seeded in the well as selected from 23 different cell types or a combination thereof.
Regarding pg. 16 of 17 of Applicant remarks, amended claim 21 of the instant application recites the following:
A tissue system comprising a three-dimensional ex vivo skeletal muscle tissue and a bioreactor, wherein the three-dimensional ex vivo skeletal muscle tissue comprises a hydrogel mixture comprising thrombin and a plurality of cells that includes skeletal muscle cells, wherein at least a portion of the cells are encapsulated inside the hydrogel, wherein the skeletal muscle tissue is characterized by one or more contractions in response to an electrical and/or chemical stimulation and the skeletal muscle tissue does not contract in the absence of electrical and/or chemical stimulation, wherein the skeletal muscle tissue comprises an A band, an I band, a Z line, a M line, and an H zone, and has substantially the same structural organization as heathy native skeletal muscle tissue, and wherein the bioreactor comprises:
a device having a well configured for growing the three-dimensional ex vivo skeletal muscle tissue from the cells seeded therein, wherein the well has a bottom; and
at least two elastic sensing elements disposed across the well such that there is a gap between the at least two elastic sensing elements and the bottom of the well, wherein the at least two elastic sensing elements are configured to: (a) permit attachment of the three-dimensional ex vivo skeletal muscle tissue formed there between, thereby suspending the three-dimensional ex vivo skeletal muscle tissue above the bottom of the well, and (b) deform in response to a contractile force exerted on the sensing elements by the three- dimensional ex vivo skeletal muscle tissue,
wherein the three-dimensional ex vivo skeletal muscle tissue is produced using a stimulation protocol comprising a plurality of pulses separated by no electrical stimulations, wherein each pulse is at least about 10 Hz applied for a duration of at least about one second.
Regarding pg. 16 of 17 of Applicant remarks, the double patenting rejection for the amended claim 21 of the instant application is sustained above, and updated with regards to now patented claims 1 and 13 of the U.S. Patent granted to Aschar-Sobbi (US 12595449).
Regarding pg. 16 of 17 of Applicant remarks, furthermore, the type of cell being used in the system is another form of intended use and manner of operation. Regarding the limitation “skeletal muscle tissue”, the material or article worked upon by the apparatus does not limit the apparatus claims. MPEP § 2115. This limitation is a manner of operating or intended use of a claimed apparatus and does not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Miklas in view of Bashir would be fully capable of operating in this manner given the structures such as a well and the at least two elastic sensing elements with a gap to the bottom of the well. Similar arguments can be made for the non-statutory double patenting rejection under modified Aschar-Sobbi.
Regarding the Declaration under 37 C.F.R. 1.132, the declaration is found unpersuasive. With respect, the points given from point 6 to point 10 refer to the Bashir reference and Bashir-related non-patent literature. Bashir has been used as a secondary reference in this rejection and is only being used for the disclosure of a thrombin-containing hydrogel mixture. The primary reference Miklas is the main reference that should be compared to the instant invention, as Miklas is the closest related prior art. Therefore, the comparison to the prior art is indirect at best. Secondly, Miklas discloses electrical stimulation (see Miklas, paragraph [0020] in general for electrically-stimulated cells) of skeletal muscle cells (see Miklas, paragraph [0177] specifically for these skeletal muscle cells).
Regarding points 11 through 13, Applicant has shown evidence that they have results, but not necessarily unexpected results, from their invention. This determination is made from the comparison to the primary reference Miklas, as described below.
Regarding point 14 of the declaration, the combination of Miklas and Bashir would not necessarily result in a low frequency optical stimulation protocol, as Miklas specifically describes an electrical stimulation protocol resulting in mature cells capable of contractions (see Miklas, paragraphs [0645]-[0647]). The frequency of the protocol is a form of intended use or manner of operating the apparatus. Regarding an intended use or manner of operating a claimed apparatus, these functions do not patentably distinguish it from the prior art. MPEP § 2114(II). The device of modified Miklas would be fully capable of operating in this manner given the electrical stimulation structure, bioreactor, and cells in the bioreactor.
Regarding point 15 of the declaration, first, the graphical results printed on the document are relatively indiscernible. It is recommended that the graphical results be printed in a similar format to those for standard drawings so that the record is clear and compact prosecution is followed. Second, under point 1), the following phrase is used to describe unexpected results:
sarcomere length (measured as the distance between Z-lines) that falls within the range of the native myofiber sarcomere length (specifically, we measured 2.36 ± 0.15μm, (see Figure A below) …
This comparison of the instant invention’s sarcomere length to native myofiber sarcomere length is incomplete as only one range of sarcomere lengths is given, while a statement of equivalency without comparison data (a positive control) is not described. Furthermore, this data and the remaining data on alleged unexpected results are not directly comparable to the Miklas invention (not an identical comparison using the same variables, such as those disclosed in Miklas paragraphs [0645]-[0647]). Even if an unidentical comparison could be drawn from the declaration’s evidence, no explanation on how this unidentical comparison relates to the Miklas invention is provided. The only evidence from the declaration that the examiner could find that was somewhat related to the Miklas reference’s frequencies of 3 Hz and 6 Hz was found in the Pallotta (“Electrical stimulation of biofidelic engineered muscle enhances myotube size, force, fatigue resistance, and induces a fast-to-slow-phenotype shift”), a non-patent literature reference attached with the declaration, in Fig. 2(e) and 2(f); however, again, no explanation was given for how this information compares to the Miklas invention. Therefore the proof for unexpected results is unpersuasive. See MPEP § 716.02(e) “Comparison With Closest Prior Art”.
Additionally, the examples given in the declaration are not commensurate in scope with the claims because in point 11 of the declaration, the pulse duration of the 10 Hz electrical stimulation – i.e. “4 ms pulse duration” – does not correlate to the claimed subject matter in claim 21. That is, “each pulse is at least about 10 Hz applied for a duration of at least about one second” (see instant claim 21, last two lines). The claimed range must show criticality to establish unexpected results, using a sufficient number of tests both inside and outside the claimed range. See MPEP § 716.02(d) “Unexpected Results Commensurate in Scope With Claimed Invention”.
Lastly, in response to Applicant’s arguments against the references individually, 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 does not show persuasive evidence as to why the examiner’s conclusion of obviousness is improper. Applicant does not persuasively argue against the reasons and/or motivation given in the rejection above to combine the prior art.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATHAN G ESPERON whose telephone number is 571-272-9807, and whose fax number is 571-273-8464. The examiner can normally be reached 9 am - 6 pm Monday through Thursday, and 9 am - 6 pm every other Friday.
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/N.G.E./Examiner, Art Unit 1799
/MICHAEL A MARCHESCHI/Supervisory Patent Examiner, Art Unit 1799
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