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
Applicant's election with traverse of Group I, claims 1-17, in the reply filed on 12/5/2025 is acknowledged.
The traversal is on the following ground(s):
1. Applicant argue that based on MPEP 803 “the claims of the present invention would appear to be part of an overlapping search area.” and “a search and examination of the entire application would not place a serious burden on the Examiner” (page 5, para 5).
This is not found persuasive because the restriction requirement is based on lack of unity under the PCT (see MPEP 823) and not the US Restriction practice in MPEP 803. The Groups identified in the restriction requirement lacked unity because the prior art of Ribeiro-Resende taught the product claims i.e. the cell constructs of Group II which was the shared technical feature between the Groups I-IV. Furthermore, as indicated by the rejections below, prior art also taught the method of Group I. Thus, the groups do not share the special technical feature which contributes over the prior art at the time the invention was made.
2. Applicant argue that Ribeiro-Resende, the prior art used in the restriction requirement to show lack of unity, does not teach the newly added claim limitation “the cells are embedded within the biocompatible matrix” and that Ribeiro-Resende “simply aligns cells with collagen fibrils or by microgrooves but does not disclose or reasonably suggest mechanical stimulation and the resultant structure obtained in the matrix” (page 5, para 6-7).
This is not found persuasive because the product claims, see Claims 19-21, do not require the newly added limitation and the product-by-process limitation argued (i.e. use of mechanical stimulation) was addressed in the restriction requirement. Specifically, that the step of mechanical stimulation in the method of claim 1 provides a structure of Bands of Bungner in the cell construct and Ribeiro-Resende teaches that their cell construct has bands of Bungner (Results: Artificial bands of Bungner on polymer filaments, Axon guidance on artificial bands of Bungner; Figure 4). Additionally, as noted above, as indicated by the rejections below, prior art also taught the method of Group I and thus the products produced by such a method. Thus, the groups do not share the special technical feature which contributes over the prior art at the time the invention was made.
The requirement is still deemed proper and is therefore made FINAL.
Claims status
Claims 24 is/are newly added. Claims 1-24 is/are currently pending with claims 18-23 is/are withdrawn. Claims 1-17, 24 is/are under examination.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 11 and 19. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim recites “contacting Schwann cells […] with a biocompatible matrix; to cultivation” (emphasis added). This phrase is grammatically incorrect. Following language is recommended:
“contacting Schwann cells […] with a biocompatible matrixfor cultivation”
OR
“contacting Schwann cells […] with a biocompatible matrix; ngthe Schwann cells […] in the biocompatible matrix”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-17, 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “wherein the cultivation is at least partially performed by administering mechanical stimulation on the cells in contact with the biocompatible matrix such that the Schwann cells or Schwann cell-like cells are embedded within the biocompatible matrix” (emphasis added). First, the phrase “cultivation is at least partially performed” is indefinite because it is unclear what is partial cultivation in the context of this method. Does the claim embrace methods wherein the cells are only partially cultivated such that additional elements are required for complete cultivation or is “partial” cultivation in reference to only exposing part of the construct to the mechanical stimulation or is “partial” cultivation in reference to only exposing the construct to the mechanical stimulation for a part of the entire cultivation duration? Second, due to the use of the phrase “such that”, it appears that claim recites an intended result of the mechanical stimulation. In other words the claim appears to recite that upon mechanical stimulation the cells embed in the matrix. No guidance is provided in the specification regarding such a mechanical stimulation. On the other hand, the specification teaches embedding the cells in the matrix and then applying mechanical stimulation (Section 5.1 on page 37). For the purpose of compact prosecution, the claim(s) 1 is/are interpreted as “wherein comprises administering mechanical stimulation on the cells in contact with the biocompatible matrix ; wherein the Schwann cells or Schwann cell-like cells are embedded within the biocompatible matrix.”
Claim 11 recites “strain treatment of 1 to 50%”. The term “%” in claim 11 is a relative term which renders the claim indefinite. The term “%” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Due to the use of this relative term, the amount of strain treatment required by this claim is indefinite.
Claims 14-16 each recite the limitation "the load axis". There is insufficient antecedent basis for this limitation in the claim.
Claim 14-16 each recite “extrinsic deformation expressed as a percentual change of length [..]” (emphasis added). It is unclear if the claim requires the extrinsic deformation to be the %change recited or is merely reciting extrinsic deformation that could be expressed as the recited % change. For the purpose of compact prosecution, the claim(s) 14-16 is/are interpreted as “extrinsic deformation of of the construct [..]”.
Claim 17 recites “wherein the construct is at least partially exposed to electrical stimulation”. It is unclear if the claims requires only part of the construct to be exposed to electrical stimulation or the claims requires the construct to be exposed to electrical stimulation for only a part of “a duration” (as opposed, for example, continuous exposure). No guidance or structure is provided in the specification that would allow for delivery of electrical stimulation to only a portion of the construct while methods from the prior art that deliver electrical stimulation for various durations were mentioned (page 18, last para). For the purpose of compact prosecution, the claim(s) 17 is/are interpreted as “wherein the construct is
Claims 2-17, 24 is/are rejected due their dependence on claim 1 because they do not clarify the 112b issue noted with claim 1.
Claim Interpretation
Claim 1 recites “Schwann cell-like cells”. The specification does not explicitly define this term however on page 5, it guides that “The present invention provides preferably cell constructs comprising primary Schwann cells, isolated from tissues, or Schwann cell-like cells differentiated from other cell types such as mesenchymal stem cells, fibroblasts or induced pluripotent stem cells etc., and a biocompatible matrix”. Thus, the broadest reasonable interpretation of “Schwann cell-like cells” are cells that are differentiated from other cell types and have some characteristic of a Schwann cell. For example, the specification teaches Adipose stem cell derived Schwann cell-like cells in Section 3 and 4 on page 34-35.
Claim Rejections - 35 USC § 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-6, 8-10, 12, 24 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Georgiou et al (Biomaterials 34 (2013) 7335-7343; IDS 12/20/2022) as evidenced by Phillips et al (Micro-structured Materials and Mechanical Cues in 3D Collagen Gels. Chapter 12: Methods Mol Biol 2011;695:183-196) and Phillips et al (TISSUE ENGINEERING, Volume 11, Number 9/10, 2005; hereinafter Phillips 2005)
Regarding claims 1 and 2, Georgiou teaches a method comprising mixing (=claimed contacting) Schwann cells with collagen gel (=claimed biocompatible matrix; =claimed protein as required for claim 2) and culturing (=claimed cultivation) the mixture to produce a cell construct (Section: 2.1. Fabrication of Schwann cell EngNT). The Schwann cells and collagen gel mixture is cultivated on a mould such that the cell-gel mixture is exposed to at least two different mechanical forces (=administer mechanical stimulation): (1) Cell-generated mechanical tension due to tethering of cell-gel mixture to the ends of the mould to “allow for alignment to develop” and, (2) Plastic compression (also mechanical force) to maintain alignment (page 7336, col. 1, para 1 and 2; Figure 1). Furthermore, since the Schwann cells were mixed with the collagen gel, the cells are embedded in the biocompatible matrix.
Regarding claim 3, in Georgiou method the culturing was performed in a culture medium in an incubator (=claimed bioreactor; Section: 2.1. Fabrication of Schwann cell EngNT).
Regarding claim 4, in Georgiou method the cell construct is in a three-dimensional sheet form that can also be rolled up to form a ring, thus the biocompatible matrix comprised in the cell construct is also in the form of a three-dimensional sheet or three-dimensional ring (Figure 1, 4, Section: 2.1. Fabrication of Schwann cell EngNT).
Regarding claims 5 and 6, in Georgiou method the tethering step that allows for cell-generated mechanical tension was performed for 1 day while the plastic compression step was performed for 1 minute (=claimed 1-60days of mechanical stimulation as required by claim 6; Section: 2.1. Fabrication of Schwann cell EngNT). Subsequently, the cell construct is further cultured for various durations, with ring-shaped constructs cultured for “upto 24 hours prior” to their use in in vivo experimentation (Section: 2.1. Fabrication of Schwann cell EngNT) and the sheet-shaped construct cultured for additional 3 days with neurons (Section: 2.4. Assessment of EngNT in co-culture with neurons). Taken together, Georgiou method comprises culturing the cell construct for various durations depending on use, with at least a 3 day duration recited for in vitro testing (=claims 3-60days of cultivation as required by claim 5).
Regarding claim 8, the specification states on page 18 that “The present constructs may be provided as bands of Bungner or Bungner-like structures with longitudinally aligned/linear bands of interdigitating Schwann cells (or Schwann-like cells) that guide regrowing axons.”. In Georgiou method the culturing is performed till the Schwann cells are longitudinally aligned (Figure 1 and 2) and this aligned construct allows for axonal guidance (Figure 5). Thus, In Georgiou method the culturing is performed till Bands of Bungner-like structure have formed.
Regarding claim 9, Georgiou teaches the construct in a three-dimensional sheet form that can also be rolled up to form a ring wherein the dimension of the construct in the ring form are 200um diameter x 15mm length (75:1 ratio; Section: 2.1. Fabrication of Schwann cell EngNT).
Regarding claim 10, Georgiou does not explicitly state that the culture steps were performed in aseptic condition however using sterile technique in cell culture is standard practice. To this end, Georgiou refers to Philip as the source of their method and Phillips evidences use of sterile technique with the very first step of the method reciting sterilization of moulds (page 187, step 1.)
Regarding claim 12, Georgiou teaches the construct of 15mm length (Section: 2.1. Fabrication of Schwann cell EngNT).
Regarding claim 24, in Georgiou method the cells in the construct align parallel to the mechanical strain produced by the tethering the construct (Figure 1). This is evidenced by Phillips 2005 that also use Schwann cell laden tethered collagen gel and state that “When the collagen is tethered at its opposite ends the cell force generates a uniaxial strain in the gel along which cells and collagen become aligned” (page 1612, col. 1, para 2).
Therefore, Georgiou anticipates the claimed invention.
Claim Rejections - 35 USC § 102/103
The text of those sections of Title 35, U.S. Code not included in this section can be found above.
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.
Claim(s) 13 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Georgiou as evidenced by Phillips, Phillips 2005, Heher et al (Acta Biomaterialia 24 (2015) 251–265; IDS 12/20/2022) and Raub et al (Acta Biomater. 2010 December ; 6(12): 4657–4665).
The teachings of Georgiou as detailed in the U.S.C. 102 rejection above are relied upon for the instant rejection.
Georgiou anticipates the method of claim 1. Georgiou’s cell construct comprises Schwann cells and a collagen matrix.
Georgiou is silent as to the Young’s modulus of their cell construct and thus Georgiou is silent whether the mechanical stimulation performed was on a construct with a Young’s modulus of 5-50kPa. The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not the cell construct of the Georgiou is distinct from, and if so to what extent, from applicant’s cell construct. Georgiou’s cell construct is similar to applicant’s construct because they both comprise Schwann cells in biocompatible matrix. In the working example, the Applicant use fibrin hydrogel while Georgiou uses a collagen hydrogel. Same as Georgiou, Applicant do not measure the Young’s modulus of their construct and thus the claimed “5-50kPa” appears to be based on previously known Young’s modulus of acellular fibrin hydrogel (see Figure 2A in Heher). To this end, Young’s modulus of acellular collagen hydrogel was known to be 0.5-12kPa (Abstract in Raub). Thus, it appears that the Young’s modulus of Georgiou’s cell construct would be 5-50kPa as claimed.
Where an examiner cannot determine whether or not the reference inherently possesses properties which anticipate, or render obvious, the claimed invention a rejection under §§102/103 is appropriate. See MPEP §§ 2112-2112.02.
The cited art taken as a whole demonstrates a reasonable probability that the cell construct of Georgiou is either identical or sufficiently similar to the claimed cell construct that whatever differences exist, they are not patentably significant. Therefore, the burden of establishing novelty or non-obviousness by objective evidence is shifted to applicants. See MPEP § 2112(v). Clear evidence the cell construct of Georgiou does not possess the claimed Young’s modulus and that Young’s modulus is a critical characteristic that is possessed by the claimed construct would advance prosecution and might permit allowance of claims. Applicant is requested to specifically point out the support for any amendments made to the disclosure and arguments in response to this Office Action, including the claims. See MPEP §§ 714.02 and 2163.06. Applicant is also requested to refer to pages and line numbers in the as-filed specification. It is noted that other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this section can be found above.
Claim(s) 7, 11, 14-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Georgiou as evidenced by Phillips, Phillips 2005 as applied to claim 1 above, and further in view of Heher et al (Acta Biomaterialia 24 (2015) 251–265; IDS 12/20/2022).
The teachings of Georgiou, Phillips, Phillips 2005 as detailed in the U.S.C. 102 rejection above are relied upon for the instant rejection.
Regarding producing Schwann cell constructs, Georgiou teaches that “The nerve autograft contains aligned Schwann cells which support and guide regenerating neurites from the proximal to the distal side of the repair site, and recreating this anisotropic 3D cellular architecture is the focus of much research in the area of peripheral nerve repair [7-9]. A range of approaches are available for achieving anisotropic engineered tissues including the use of aligned fibres or channels, patterned surfaces, electrical and magnetic fields, mechanical loading and gradients of physical and chemical cues to organize engrafted and/or infiltrating cells.” (page 7335, col. 2, para 1, 2). Thus, Georgiou teaches that various means to generate aligned cell constructs, including mechanical loading, were already known and they present an “alternative approach” that also confers alignment using a tethered collagen approach (page 7335, col. 2, para 3).
Regarding static and ramp strain, the specification states that “Static strain treatment is defined as a constant stretch/elongation of the construct by a defined length, whereas in ramp strain, the extent of stretch exerted on the construct is continuously or step-wise increased.” (page 18).
To this end, in Georgiou method, as evidenced by Phillips 2005, the tethering step that allows for cell-generated mechanical tension results in a static strain along an axis.
Georgiou’s method does not comprise a static or a ramp strain wherein the construct is stretched/elongated by a defined length, as required by claim 7. Furthermore, Georgiou’s method does not comprise deformation of the construct by a pre-defined percentual change as recited in claims 11, 14-16.
However, means of mechanical deformation wherein a cell construct is stretched by a defined length to produce an aligned cell construct were known in the art.
Heher teaches a bioreactor system that allows for mechanical deformation of cell constructs by a defined length, being able to produce both static and ramp strain with various % change in construct length (Section: 2.3. MagneTissue bioreactor system, Figure 1, 2B; as required by claim 7). Heher exemplify the use of their bioreactor to generate aligned muscle construct using 10% and 3% static strain (as required by claims 11, 14-16).
The combination of prior art cited above under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S., 82 USPQ2d 1385 (2007). Exemplary rationales that may support a conclusion of obviousness are from MPEP 2143.
In the present situation, rationale (G) is applied - Some Teaching, Suggestion, or Motivation in the Prior Art That Would Have Led One of Ordinary Skill To Modify the Prior Art Reference or To Combine Prior Art Reference Teachings To Arrive at the Claimed Invention.
MPEP 2143 guides that for rationale G “Office personnel must articulate the following: (1) a finding that there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings; (2) a finding that there was reasonable expectation of success; and (3) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
In the instant case:
(1) The prior art of Georgiou teaches a cell construct comprising Schwann cells and a biocompatible matrix. Georgiou’s method to produce the cell construct comprises tethering the cell construct to produced alignment in the embedded Schwann cells. However, Georgiou also teaches that other means for producing aligned constructs were known, such as mechanical loading. Furthermore, Georgiou taught that methods for producing aligned constructs need not be cell specific – teaching anisotrophy/alignment as a key feature of various tissues and suggesting the utility of their own method to produce aligned constructs from any suitable alternative cell (page 7335, col. 1, para 1; page 7336, col. 1, para 1; Conclusion). Thus, Georgiou suggested other alternative means, such as mechanical stimulation, could be used to generate aligned Schwann cell constructs.
To this end, Heher taught an alternative means to produce alignment in cells embedded in a biocompatible matrix. Heher teaches a method comprising providing a mechanical stimulation of a construct by stretching the construct by a defined length. When comparing their method to methods comprising tethering the cell construct, Heher teaches that “The majority of previously reported 3D skeletal muscle engineering approaches use scaffold anchoring as the primary source of strain to generate alignment, with the limitation that the extent and type of strain cannot be properly controlled.” (page 252, col. 2, para 1). Thus, Heher motivates an ordinary artisan to use their more controlled approach as opposed to alternatives, such as of Georgiou, wherein mechanical stimulation is provided by tethering/anchoring the construct and thus cannot be predefined, as in Heher.
Taken together, Georgiou and Heher provide sufficient teaching, suggestion and motivation to an ordinary artisan to produce aligned Schwann cell constructs using Heher’s bioreactor system.
(2) An ordinary artisan reasonably expects to use Heher’s bioreactor system to produce an aligned Schwann cell construct by mixing Schwann cells with Heher’s biocompatible matrix and use it in Heher’s bioreactor system to provide mechanical stimulation. Since Georgiou teaches that mechanical stimulation produces alignment in Schwann cell constructs, an ordinary artisan reasonably expects that use of Heher’s bioreactor system on Schwann cell comprising constructs would also result in alignment in Schwann cell comprising constructs.
Therefore, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR. Therefore, it would be obvious to a person of ordinary skill in the art to use Schwann cells, such as taught by Georgiou, in the bioreactor system of Heher, with a reasonable expectation to produce an aligned Schwann cell construct.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Georgiou as evidenced by Phillips and Phillips 2005 as applied to claim 1 above, and further in view of Anderson et al (Crit Rev Biomed Eng. 2015 ; 43(2-3): 131–159; IDS 12/20/2022).
The teachings of Georgiou, Phillips, Phillips 2005 as detailed in the U.S.C. 102 rejection above are relied upon for the instant rejection.
Georgiou teaches the method of claim 1.
Georgiou does not teach exposing the construct to electrical stimulation.
Anderson teaches that electrical stimulation of Schwann cells increases secretion of neurotrophic factors from these cells and suggests electrical stimulation of Schwann cell constructs to promote peripheral nerve regeneration (page 14, para 3; Figure 15).
Therefore, based on Anderson’s teachings, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to electrically stimulate Georgiou’s Schwann cell construct. An ordinary artisan would be motivated to electrically stimulate Georgiou’s Schwann cell construct to increase neurotrophic factors secretion from the construct. An ordinary artisan reasonably expects to deliver electrical stimulation to a Schwann cell construct using nerve growth conduits already known in the art (see Table 3 of Anderson).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Conclusion
No claim is allowed.
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/MATASHA DHAR/Examiner, Art Unit 1632