DETAILED ACTION
Status of Claims
Claims 1-3, 5-6, 8, 10, 12-13, 15, 17-18, 20, 22-25, 28, 30 and 61 are currently pending and are the subject of this Office Action. This is the first Office Action on the merits of the claims. 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 Office Action: Non-Final
Claim Rejections – 35 U.S.C. § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. § 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 30 is rejected under 35 U.S.C. § 102(a)(2) as being anticipated by KUSHNIR (WO 2022/180627 A1, Publ. Sep. 01, 2022; Filed Feb. 23, 2021; on 07/01/2024 IDS; hereinafter, “Kushnir”).
Kushnir is directed to:
Title: KIT FOR TREATING DAMAGED NERVES
Abstract: The present disclosure provides a method and a kit for inducing growth or regeneration of a damaged nerve of a subject, or the treatment thereof by applying a clot of blood that is withdrawn from the subject. The blood that is withdrawn from the subject is introduced to a lumen of a nerve enveloping hollow element that envelopes the damaged portion of the nerve while controllably coagulating within the lumen to form a clot on the damaged portion of the nerve. The clot, while in physical contact with the damaged portion of the nerve, enhances the rehabilitation of the nerve and may partially or fully restore its functionality.
Kushnir, title & abstract. In this regard, Kushnir discloses a claim embodiment drawn to kit for inducing growth or regenerating a damaged nerve portion of a subject, and method of enveloping a damaged nerve portion with a nerve enveloping hollow element having a lumen such that said damaged nerve portion resides in said lumen, and introducing blood of a subjected into said lumen:
1. A kit for inducing growth or regenerating a damaged nerve portion of a subject,
the kit comprising:
a nerve enveloping hollow element having a lumen for enveloping said damaged nerve portion such that said portion resides in at least a portion of said lumen;
one or more blood withdrawal devices for allowing withdrawal of blood from the
subject;
one or more blood collection receptacles for receiving the blood withdrawn from
the subject;
a coagulation assembly configured for permitting mixture of the withdrawn blood with one or more coagulation inducers for initiating coagulation process of the withdrawn blood; and
an applicator for introducing the incomplete coagulated blood into said lumen.
[…]
7. The kit of any one of claims 1-6, for use in a method for treating, inducing growth, or regenerating a damaged nerve portion, the method comprising:
(i) enveloping said damaged nerve portion with a nerve enveloping hollow element having a lumen such that said damaged nerve portion resides in said lumen;
(ii) withdrawing whole blood from the subject;
(iii) mixing the subject’s blood with one or more coagulation inducers;
(iv) prior to complete coagulation of the blood, introducing the blood with the coagulation agent into said lumen; and
(v) permitting the blood to coagulate in said lumen.
Kushnir, claims 1 and 7.
Regarding independent claim 30 and the requirements:
30. ([…]) A method of preparing a personalized nerve graft comprising, contacting a surface of a nerve graft scaffold with an undiluted whole blood sample from a subject in need of the personalized nerve graft.
Kushnir clearly teaches enveloping a damaged nerve portion with a nerve enveloping hollow element having a lumen such that said damaged nerve portion resides in said lumen, and introducing blood of a subjected into said lumen (Kushnir, claims 1 and 7), WHEREBY it is noted:
“said damaged nerve portion with a nerve enveloping hollow element having a lumen such that said damaged nerve portion resides in said lumen” (Kushnir, claim 7) reads on a “nerve graft scaffold” of claim 30; and
“whole blood from the subject” (Kushnir, claim 7) reads on an “undiluted whole blood sample from a subject in need of the personalized nerve graft” of claim 30;
wherein “prior to complete coagulation of the blood, introducing the blood with the coagulation agent into said lumen” (Kushnir, claim 7) reads on the active step requirements of claim 30 for “contacting a surface of a nerve graft scaffold with an undiluted whole blood sample.”
With respect to an an “undiluted whole blood sample” of claim 30, although Kushnir teaches “(iii) mixing the subject’s blood with one or more coagulation inducers” (Kushnir, claim 7), Kushnir also teaches coagulation inducers within the blood collection receptacles of Kushnir’s kit (Kushnir, p. 5, ln. 30-31, “[i]n some embodiments of the kit, the one or more coagulation inducer(s) are comprised within said one or more blood collection receptacle”), in powder form (Kushnir, p. 7, ln. 28-30, “[i]n some embodiments of the nerve graft aspect method, said one or more coagulation inducer(s) are in powder form”), therefore Kushnir’s steps (ii) and (iii) (Kushnir, claim 7) does not require any further liquid dilution, thereby reading on an “undiluted whole blood sample” of claim 30.
Thus, Kushnir anticipates claim 30.
Claim Rejections – 35 U.S.C. § 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. § 103(a) 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 C.F.R. § 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 1-2, 5-6, 8, 10, 12-13, 15, 17-18, 20 and 22-25 are rejected under 35 U.S.C. § 103 as being unpatentable over GILBERT (US 2017/0072100 A1, Publ. Mar. 16, 2017; on 07/01/2024 IDS; hereinafter, “Gilbert”).
Gilbert is directed to:
METHOD AND APPARATUS FOR DECELLULARIZATION OF TISSUE
ABSTRACT
Methods of decellularization of tissue, such as mammalian tissue, are provided, along with methods of making an extracellular matrix (ECM) preparation. Systems and apparatus useful in performing the methods are also provided.
Gilbert, title & abstract. In this regard, Gilbert teaches “methods of making decellularized ECM material” by “application of a pressure differential to the tissue,” wherein “the tissue is placed in a hypertonic or a hypotonic solution”:
SUMMARY
[0006] Provided herein are methods of making decellularized ECM material. The material is decellularized by application of a pressure differential to the tissue to be decellularized, such as a cyclical pressure differential, resulting in an ECM material that is superior in many instances to ECM materials decellularized by other methods, such as by use of boiling water, agitation, or acids, which can damage the end-product. According to certain embodiments, the tissue is placed in a hypertonic or a hypotonic solution that optionally contains one or more of a detergent; an enzyme; and/or an acid, such as peracetic acid. Also provided is a system or apparatus comprising a vacuum chamber including a tissue cassette, optionally comprising a tissue sample to be decellularized.
[0007] A method of decellularizing tissue is provided. The method comprises changing a pressure at least one time to decellularize the tissue sample. The pressure is changed by any useful method, such as by changing pressure within an airtight chamber. Thus, according to one embodiment, the tissue sample is placed into an airtight chamber and pressure is changed in the container. An airtight container may be any size, ranging, for example and without limitation, from a small bench-top vacuum chamber, such as the chamber shown in connection with the examples below, to a room-sized container, e.g., a room, facilitating bulk decellularization of large quantities of tissue. In one embodiment, the tissue sample is immersed in a decellularization solution and is optionally agitated during application of the pressure change. Non-limiting examples of a decellularization solution is an aqueous solution such as water, phosphate-buffered saline (PBS) or saline. According to further embodiments, the solution further comprises one or more of a surfactant, a salt, a sugar, an acid, a protease, or a DNAse, for example and without limitation the decellularization solution is an aqueous solution comprising one or more of: SDS; CHAPS; deoxycholate; Triton X-100; Trypsin; DNAse; Proteinase K; NaCl; glucose; urea; or peracetic acid. In one embodiment, the decellularization solution comprises Triton X-100 and NaCl. According to one embodiment, the method further comprises after changing the pressure in the chamber at least one time, agitating the tissue in a solution comprising peracetic acid and ethanol. In one embodiment, the pressure is changed cyclically with a frequency of from 5 seconds to one hour, for example the pressure is changed cyclically with a frequency of from 5 seconds to 30 minutes and in one embodiment from 1 to 2 minutes. The duty cycle, a ratio of the time it takes to pressurize or evacuate to how long a pressure is held, ranges in one embodiment from 15% to 90%. In one embodiment, relative pressure ramp rates, that is the rate of pressure change during pressurization or evacuation, ranges from 0.25 MPa/s to 0.0001 MPa/s. In one embodiment, the pressure is changed at least about 10% or at least about 25%. For example a change of pressure from 1 atm to 2 atm is a 200% change, a change from 2 atm to 0.5 atm is a 75% change, a change of from 2 atm to 1 atm is a 50% change, and a change of from 0.5 atm to 2 atm is a 400% change. The pressures may range above or below ambient, environmental pressure, such as above or below 1 atm or 0.1013 MPa. In another embodiment, the pressure is changed at least about 0.10 MPa, or at least about 0.25 MPa. A typical absolute pressure range is from 0.93 MPa to 0.006 MPa, and values and increments therebetween.
[0008] Also provided is a method of preparing an ECM material, comprising decellularizing tissue according to any method described herein, and sterilizing, packaging and/or drying, cryopreserving, freezing or lyophilizing the decellularized tissue. In one embodiment, the method comprises decellularizing the tissue and sterilizing, packaging and drying, cryopreserving, freezing or lyophilizing the decellularized tissue.
Gilbert, par. [0006]-[0008].
Regarding independent claim 1 and the requirements:
1. ([…]) A method of preparing an immunologically anonymized nerve segment, comprising:
non-chemically removing cells from a nerve segment; and
enzymatically removing immunogenic remnants from the nerve
provide a immunologically anonymized nerve segment.
Gilbert clearly teaches “methods of making decellularized ECM material” by “application of a pressure differential to the tissue,” wherein “the tissue is placed in a hypertonic or a hypotonic solution” (Gilbert, par. [0006]-[0008]), WHEREBY it is noted:
“application of a pressure differential to the tissue,” wherein “the tissue is placed in a hypertonic or a hypotonic solution,” wherein “[n]on-limiting examples of a decellularization solution is an aqueous solution such as […] or saline,” e.g., “NaCl” (Gilbert, par. [0007]) relates to the active step of claim 1 for “non-chemically removing cells”;
“application of a pressure differential to the tissue,” wherein “the tissue is placed in a hypertonic or a hypotonic solution,” wherein “[a]ccording to further embodiments, the solution further comprises one or more of a […], or a DNAse” (Gilbert, par. [0007]) relates to the active step of claim 1 for “enzymatically removing immunogenic remnants,” as well as the requirements of claim 12 for “exposing the nerve segment to an enzyme solution” and claim 13 for “DNase”:
12. ([…]) The method of claim 1, wherein the enzymatically removing comprises exposing the nerve segment to an enzyme solution.
13. ([…]) The method of claim 12, wherein the enzyme solution comprises DNase.
It is further noted that Gilbert teaches “Additional Tissues” for processing, inter alia, “CNS (optic nerve, brain, spinal cord, peripheral nerve, dura mater)”:
Additional Tissues
[0069] In addition to trachea, airway (trachea and vocal fold); esophagus; liver; small or large intestine; dermis; cardiovascular (myocardium, heart valve, and both thoracic and abdominal aorta); and ocular (retina) tissue have been similarly successfully processed. CNS (optic nerve, brain, spinal cord, peripheral nerve, dura mater); peripheral vasculature; orthopaedic (nucleus polposus, cartilage (TMJ, knee meniscus), tendon, bone); skeletal muscle; pancreas; and lung tissue are processed in a similar manner.
(Gilbert, par. [0069]), which encompasses a “nerve segment” of claim 1; however, Gilbert DOES NOT EXPRESSLY TEACH an exemplary embodiment thereof with sufficient specificity in order to be anticipatory, and therefore, would be obvious per Gilbert’s broader disclosure. In this regard, it is noted that a reference is analyzed using its broadest teachings. MPEP § 2123 [R-5] states: “[W]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007)(quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious”, the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to rearrange the disclosed above cited steps of Gilbert in order to arrive at “methods of making decellularized ECM material” by “application of a pressure differential to the tissue,” wherein “the tissue is placed in a hypertonic or a hypotonic solution” (Gilbert, par. [0006]-[0008]), wherein the tissue is “CNS (optic nerve, brain, spinal cord, peripheral nerve, dura mater)” (Gilbert, par. [0069]).
Thus, Gilbert renders claims 1 and 12-13 obvious.
Regarding claim 2 and the requirements:
2. ([…]) The method of claim 1, wherein the nerve segment is derived from a human or an animal species.
Gilbert teaches “[i]n certain embodiments, the ECM is isolated from a vertebrate animal, for example and without limitation, human, monkey, pig, cattle, and sheep” (Gilbert, par. [0027]), which encompasses “a human or an animal species” of claim 2.
Thus, Gilbert renders claim 2 obvious.
Regarding claims 5-6 and 8 and the requirements:
5. The method of claim 1, wherein said non-chemically removing comprises exposing the nerve segment to a salt solution having a cell disrupting effective concentration of a salt.
6. ([…]) The method of claim 5, wherein the salt comprises KCl, MgCl2, NaCl or a combination thereof.
[…]
8. The method of claim 5, wherein the concentration of the salt in the salt solution is from 0.5 M to 2.0 M.
Gilbert teaches “first soaking the tissue in a de-epithelializing solution such as hypertonic saline,” e.g., “1.0 N saline”:
[0035] In another embodiment, the epithelial cells are delaminated first by first soaking the tissue in a de-epithelializing solution such as hypertonic saline, for example and without limitation, 1.0 N saline, for periods of time ranging from 10 minutes to 4 hours. Exposure to hypertonic saline solution effectively removes the epithelial cells from the underlying basement membrane. […].
(Gilbert, par. [0035]), which is a “salt” of claims 5-6 and 8, “NaCl” of claim 6, and 1.0 M salt of claim 8. In this regard, it is noted that MPEP § 2144.05 (I), states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art' a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d, 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Thus, Gilbert renders claims 5-6 and 8 obvious.
Regarding claim 10 and the requirements:
10. The method of claim 1, wherein said non-chemically removing further comprises exposing the nerve segment to a non-osmotic liquid.
Gilbert teaches: “During decellurization and during the application of a pressure change, the tissue to be decellularized is placed in a hypotonic, a hypertonic or an isotonic decellularization solution and is optionally agitate, e.g., on a shaker” (Gilbert, par. [0038]), which encompasses “exposing the nerve segment to a non-osmotic liquid” of claim 10.
Thus, Gilbert renders claim 10 obvious.
Regarding claim 15 and the requirements:
15. ([…]) The method of claim 1, wherein said non-chemically removing and said enzymatically removing are performed sequentially.
it is noted that MPEP § 2144.04 (IV)(C) states that changes in sequence of adding ingredients are obvious, absent evidence of new or unexpected results: “Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious.).” Nonetheless, Gilbert teaches “de-epithelializing solution such as hypertonic saline, for example and without limitation, 1.0 N saline, for periods of time ranging from 10 minutes to 4 hours,” and then “next subjected to further treatment to remove the majority of abluminal tissues but not the epithelial basement membrane,” e.g., “by mechanical abrasion or by a combination of enzymatic treatment, hydration, and abrasion”:
[0035] In another embodiment, the epithelial cells are delaminated first by first soaking the tissue in a de-epithelializing solution such as hypertonic saline, for example and without limitation, 1.0 N saline, for periods of time ranging from 10 minutes to 4 hours. Exposure to hypertonic saline solution effectively removes the epithelial cells from the underlying basement membrane. The tissue remaining after the initial delamination procedure includes epithelial basement membrane and the tissue layers abluminal to the epithelial basement membrane. This tissue is next subjected to further treatment to remove the majority of abluminal tissues but not the epithelial basement membrane. The outer serosal, adventitial, smooth muscle tissues, tunica submucosa and most of the muscularis mucosa are removed from the remaining de-epithelialized tissue by mechanical abrasion or by a combination of enzymatic treatment, hydration, and abrasion.
(Gilbert, par. [0035]), which meets the requirement of claim 15 for “performed sequentially.”
Thus, Gilbert renders claim 15 obvious.
Regarding claims 17-18, 20 and 22 and the requirements:
17. ([…]) The method of claim 1, further comprising eluting waste products of said non-chemically removing and/or said enzymatically removing from the nerve segment.
18. ([…]) The method of claim 17, wherein said eluting comprises washing the segment with phosphate-buffered saline.
[…]
20. ([…]) The method of claim 1, further comprising sterilizing the immunologically anonymized nerve segment in a peracetic acid solution.
[…]
22. ([…]) The method of claim 20, further comprising washing the immunologically anonymized nerve segment in phosphate-buffered saline after sterilization.
Gilbert teaches “Decellularization” involving:
[0054] Decellularization. Tracheas were trimmed of extra tissue under a dissecting microscope (Zeiss StemiDV4) and were then frozen at −80° C. until time for surgery. The tracheas were thawed in deionized water at room temperature. Tracheas were then decellularized with fourteen 90-minute cycles each consisting of deionized water, then 3% Triton X-100, and then 3M NaCl treatments, leaving a decellularized tracheal scaffold. During this process, tracheas were subjected to cyclical pressure changes between room atmosphere and vacuum in a custom apparatus. For this experiment, the chamber was evacuated from ~0.1 MPa to 0.02 MPa in 20 seconds, held for 20 seconds, and then was pressurized from 0.02 MPa to ~0.1 MPa in 20 seconds. Finally, the decellularized scaffolds were agitated at 200 RPM on a shaker in a 0.1% peracetic acid (PAA)/4% ethanol solution for 90 minutes at 4° C. followed by three 30 minutes rinses in phosphate buffered saline (PBS), shaken at 200 RPM at 4° C. Scaffolds were then individually packaged in physiologic saline, and terminally sterilized by exposure to 20 kGy gamma irradiation.
(Gilbert, par. [0054]), whereby it is noted:
the step, wherein “three 30 minutes rinses in phosphate buffered saline (PBS), shaken at 200 RPM at 4° C” (Gilbert, par. [0054]) relates to “eluting” of claims 17-18, “washing the segment with phosphate-buffered saline” of claim 18, and “washing the immunologically anonymized nerve segment in phosphate-buffered saline” of claim 22; and
the step, wherein “the decellularized scaffolds were agitated at 200 RPM on a shaker in a 0.1% peracetic acid (PAA)/4% ethanol solution for 90 minutes at 4° C” (Gilbert, par. [0054]) relates to “sterilizing the immunologically anonymized nerve segment in a peracetic acid solution” of claim 20;
wherein the sequence, “[f]inally, the decellularized scaffolds were agitated at 200 RPM on a shaker in a 0.1% peracetic acid (PAA)/4% ethanol solution for 90 minutes at 4° C. followed by three 30 minutes rinses in phosphate buffered saline (PBS), shaken at 200 RPM at 4° C” (Gilbert, par. [0054]), relates to “washing the immunologically anonymized nerve segment in phosphate-buffered saline after sterilization” of claim 22.
Since it would be obvious to arrive at Gilberts “methods of making decellularized ECM material” (Gilbert, par. [0006]-[0008]), wherein the tissue is “CNS (optic nerve, brain, spinal cord, peripheral nerve, dura mater)” (Gilbert, par. [0069]), as discussed above, one would have been further modified to agitate in PAA followed by rinsing in PBS (Gilbert, par. [0054]). See MPEP § 2123 [R-5] regarding the obviousness of rearranging a reference according to the teachings of that same reference.
Thus, Gilbert renders claims 17-18, 20 and 22 obvious.
Regarding claim 23 and the requirements:
23. ([…]) The method of claim 1, further comprising cryopreserving the immunologically anonymized nerve graft.
Gilbert teaches: “In one embodiment, the method comprises decellularizing the tissue, sterilizing, and drying, cryopreserving, freezing or lyophilizing the decellularized tissue” (Gilbert, par. [0041]), which encompasses “cryopreserving” of claim 23. See MPEP § 2123 [R-5] regarding the obviousness of rearranging a reference according to the teachings of that same reference.
Thus, Gilbert renders claim 23 obvious.
Regarding claim 24 and the requirements:
24. ([…]) An immunologically anonymized nerve graft prepared according to claim 1.
it would be obvious to rearrange the disclosed above cited steps of Gilbert in order to arrive at “methods of making decellularized ECM material” by “application of a pressure differential to the tissue,” wherein “the tissue is placed in a hypertonic or a hypotonic solution” (Gilbert, par. [0006]-[0008]), wherein the tissue is “CNS (optic nerve, brain, spinal cord, peripheral nerve, dura mater)” (Gilbert, par. [0069]), thereby resulting the “immunologically anonymized nerve graft” of claim 24.
Thus, Gilbert renders claim 24 obvious.
Regarding claim 25 and the requirements:
25. ([…]) A method of regenerating a nerve defect, comprising implanting the immunologically anonymized nerve graft prepared by claim 1.
Gilbert teaches claims embodiments directed to:
1. A method of decellularizing a tissue sample, comprising:
a) placing the tissue sample in an airtight chamber; and
b) cyclically changing pressure over at least one cycle in an environment in which the tissue sample is placed, thereby decellularizing the tissue sample.
[…]
20. A method of producing tissue in a patient, comprising implanting in the patient a decellularized tissue prepared according to the method of claim 1.
Gilbert, claims 1 and 20. Since it would be obvious to rearrange the disclosed above cited steps of Gilbert in order to arrive at “methods of making decellularized ECM material” by “application of a pressure differential to the tissue,” wherein “the tissue is placed in a hypertonic or a hypotonic solution” (Gilbert, par. [0006]-[0008]), wherein the tissue is “CNS (optic nerve, brain, spinal cord, peripheral nerve, dura mater)” (Gilbert, par. [0069]), one would be further motivated to implant the decellularized tissue into a patient (Gilbert, claims 1 and 20), thereby meeting the active step of claim 25 for “implanting the immunologically anonymized nerve graft prepared by claim 1.” See MPEP § 2123 [R-5] regarding the obviousness of rearranging a reference according to the teachings of that same reference.
Thus, Gilbert renders claim 25 obvious.
Claim 3 is rejected under 35 U.S.C. § 103 as being unpatentable over GILBERT (US 2017/0072100 A1, Publ. Mar. 16, 2017; on 07/01/2024 IDS; hereinafter, “Gilbert”), as applied to claims 1-2, 5-6, 8, 10, 12-13, 15, 17-18, 20 and 22-25, above, and further in view of BUCKENMEYER (Buckenmeyer, et al., Decellularization techniques and their applications for the repair and regeneration of the nervous system, Methods 171 (2020) pp. 41-61; on 07/01/2024 IDS; hereinafter, “Buckenmeyer”).
The teachings of Gilbert, as set forth above, are hereby incorporated. However, GILBERT DOES NOT EXPRESSLY TEACH “prior to said non-chemically removing, snap-freezing the nerve segment” as required by claim 3:
3. ([…]) The method of claim 1, further comprising prior to said non-chemically removing, snap-freezing the nerve segment.
which is well within the purview of the ordinarily skilled artisan.
Buckenmeyer, for instance, is directed to:
Decellularization techniques and their applications for the repair and regeneration of the nervous system
ABSTRACT
A variety of surgical and non-surgical approaches have been used to address the impacts of nervous system injuries, which can lead to either impairment or a complete loss of function for affected patients. The inherent ability of nervous tissues to repair and/or regenerate is dampened due to irreversible changes that occur within the tissue remodeling microenvironment following injury. Specifically, dysregulation of the extracellular matrix (i.e., scarring) has been suggested as one of the major factors that can directly impair normal cell function and could significantly alter the regenerative potential of these tissues. A number of tissue engineering and regenerative medicine-based approaches have been suggested to intervene in the process of remodeling which occurs following injury. Decellularization has become an increasingly popular technique used to obtain acellular scaffolds, and their derivatives (hydrogels, etc.), which retain tissue-specific components, including critical structural and functional proteins. These advantageous characteristics make this approach an intriguing option for creating materials capable of stimulating the sensitive repair mechanisms associated with nervous system injuries. Over the past decade, several diverse decellularization methods have been implemented specifically for nervous system applications in an attempt to carefully remove cellular content while preserving tissue morphology and composition. Each application-based decellularized ECM product requires carefully designed treatments that preserve the unique biochemical signatures associated within each tissue type to stimulate the repair of brain, spinal cord, and peripheral nerve tissues. Herein, we review the decellularization techniques that have been applied to create biomaterials with the potential to promote the repair and regeneration of tissues within the central and peripheral nervous system.
Buckenmeyer, title & abstract. In this regard, Buckenmeyer discloses mechanical based methods for decellularization including “freeze-thaw cycles” in combination with other methods including a combination of water or PBS washes and DNase I:
2.3. Mechanical based methods
Another major goal of decellularization methods is to maintain the native ECM structure and composition. Therefore, a balance must be found between sufficient removal of immunogenic material and preservation of the ECM. Mechanical methods such as physical delamination or multiple freeze-thaw cycles can effectively remove dense cell regions or lyse cells, allowing for less harsh chemical treatments. While mechanical methods alone have been used successfully in a few tissues, they are often used in conjunction with chemical or enzymatic methods because they are ineffective at clearing genetic material from a scaffold after cell lysis. Excessive physical decellularization methods can also disrupt the natural ECM ultrastructure and alter mechanical properties.
Freeze-thaw cycles can cause cell lysis while still maintaining mechanical integrity as well as ECM matrix components such as collagen and GAGs. However, freeze-thaw cycles alone are insufficient at removing genetic material after cell lysis in most cases [177]. Similarly, the use of high hydrostatic pressure is another mechanical method that can be beneficial if used under specific conditions. Pressures greater than 600 MPa have been applied to tissues to destroy cell membranes [178], [179]. For both, a combination of water or PBS washes and DNase I are used to break down and wash away fragments while removing any remaining genetic material; however, high pressures can denature or deform ECM proteins [180].
(Buckenmeyer, p. 45, par. 1-2), e.g., freeze thawing at -80ºC (Buckenmeyer, p. 47, Table 2, Porcine Brain), which relates to “prior to said non-chemically removing, snap-freezing the nerve segment” of claim 3.
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to perform Gilbert’s “methods of making decellularized ECM material” by “application of a pressure differential to the tissue,” wherein “the tissue is placed in a hypertonic or a hypotonic solution” (Gilbert, par. [0006]-[0008]) and treatment with“DNase” (Gilbert, par. [0007]), and to have performed “freeze-thaw cycles” prior to treatment per Buckenmeyer ((Buckenmeyer, p. 45, par. 1-2). One would have been motivated to do so with a reasonable expectation of success in order to obtain the advantage of a suitable mechanical treatment for decellularization (Buckenmeyer, p. 45, par. 1-2). See MPEP § 2144.07 stating that the selection of a known material based on its suitability for its intended use is prima facie obvious, which cites Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945), wherein “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle.”
Thus, the prior art renders claim 3 obvious.
Claims 28 and 61 are rejected under 35 U.S.C. § 103 as being unpatentable over KUSHNIR (WO 2022/180627 A1, Publ. Sep. 01, 2022; Filed Feb. 23, 2021; on 07/01/2024 IDS; hereinafter, “Kushnir”), in view of STREHL (WO 2020/026212 A2, Publ. Feb. 02, 2020; on 07/01/2024 IDS; hereinafter, “Strehl”).
The teachings of Kushnir, as set forth in the above rejection of claim 30 under 35 U.S.C. § 102 (a)(2) are hereby incorporated. Regarding independent claim 28 and the requirements:
28. ([…]) A method of preparing a personalized nerve graft comprising contacting a nerve graft scaffold with a suspension comprising a whole blood sample from a subject in need of the personalized nerve graft, wherein the whole blood sample is diluted in a physiological solution.
Kushnir clearly teaches enveloping a damaged nerve portion with a nerve enveloping hollow element having a lumen such that said damaged nerve portion resides in said lumen, and introducing blood of a subjected into said lumen (Kushnir, claims 1 and 7), WHEREBY it is noted:
“said damaged nerve portion with a nerve enveloping hollow element having a lumen such that said damaged nerve portion resides in said lumen” (Kushnir, claim 7) reads on a “nerve graft scaffold” of claim 28; and
“whole blood from the subject” (Kushnir, claim 7) reads on a “whole blood sample from a subject in need of the personalized nerve graft” of claim 30;
wherein “prior to complete coagulation of the blood, introducing the blood with the coagulation agent into said lumen” (Kushnir, claim 7) reads on the active step requirements of claim 30 for “contacting a nerve graft scaffold.”
However, Kushnir DOES NOT EXPRESSLY TEACH a “suspension comprising a whole blood sample,” wherein “the whole blood sample is diluted in a physiological solution,” as required by claim 28, which is well within the purview of the ordinarily skilled artisan.
Strehl, for instance, is directed to:
Title: METHODS OF PREPARING PERSONALIZED BLOOD VESSELS
Abstract: The present disclosure relates to methods of preparing personalized blood vessels, useful for transplantation with improved host compatibility and reduced susceptibility to thrombosis. Also provided are personalized blood vessels produced by the methods and use thereof in surgery.
Trehl, title & abstract. In this regard, Strehl teaches “contacting a surface of an acellular tubular scaffold with an undiluted whole blood sample” or a “whole blood sample [that] is diluted in a physiological solution”:
SUMMARY OF THE DISCLOSURE
[06] One aspect of the present disclosure relates to a method of preparing a personalized blood vessel comprising, contacting a surface of an acellular tubular scaffold with an undiluted whole blood sample from a subject in need of the personalized blood vessel, wherein the contacting is performed for more than 2 days.
[07] Another aspect of the present disclosure relates to a method of preparing a personalized blood vessel, comprising contacting a surface of an acellular tubular scaffold with a suspension comprising a whole blood sample from a subject in need of the personalize blood vessel, wherein the whole blood sample is diluted in a physiological solution. In some embodiments, the physiological solution maintains colloid oncotic pressure of the extracellular environment, buffers the pH in a CO2 independent mantter, and/or provides a cell protective or antioxidant effect.
(Strehl, par. [0006]-[0007]), wherein a”suspension” of “whole blood sample [that] is diluted in a physiological solution” (Strehl, par. [0007]) is a “suspension” of a “whole blood sample [that] is diluted in a physiological solution” of claim 28.
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to perform Kushnir’s steps (ii) and (iii) (Kushnir, claim 7) with “whole blood” that is “diluted in a physiological solution” per Stehl (Strehl, par. [0006]-[0007]). One would have been motivated to do so with a reasonable expectation of success in order to obtain the advantage of “preparing personalized blood vessels, useful for transplantation with improved host compatibility and reduced susceptibility to thrombosis.” Kushnir, abstract. Further, Kushnir teaches an overlapping set of overlapping blood samples including a “whole blood sample [that] is diluted in a physiological solution” (Strehl, par. [0007]) and “undiluted whole blood sample” (Strehl, par. [0006]), the latter related to Kushnir’s “whole blood from the subject” (Kushnir, claim 7), thereby establishing diluted and undiluted blood samples as functional equivalents for “preparing personalized blood vessels, useful for transplantation” (Stehl, abstract). Regarding equivalents known for the same purpose, MPEP § 2144.06 (II) states: “An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).”
Thus, the prior art renders claim 28 obvious.
Regarding claim 61 and the requirements:
61. ([…]) A method of regenerating a nerve defect, comprising implanting the personalized nerve graft prepared by claim 28 to the subject, whose blood was used for preparing the personalized nerve graft.
Kushnir teaches a “method for treating, inducing growth, or regenerating a damaged nerve portion” involving “(i) enveloping said damaged nerve portion with a nerve enveloping hollow element having a lumen such that said damaged nerve portion resides in said lumen,” and “(iv) prior to complete coagulation of the blood, introducing the blood with the coagulation agent into said lumen” (Kushnir, claim 7), which meets the active step requirements of claim 61 for “implanting” a “personalized nerve graft.”
Thus, the prior art renders claim 61 obvious.
Conclusion
Claims 1-3, 5-6, 8, 10, 12-13, 15, 17-18, 20, 22-25, 28, 30 and 61 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOMINIC LAZARO whose telephone number is (571)272-2845. The examiner can normally be reached on Monday through Friday, 8:30am to 5:00pm EST; alternating Fridays out.
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/DOMINIC LAZARO/Primary Examiner, Art Unit 1611