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 .
Claim Status
Claims 1-39 are pending.
Claims 1-25, and 30-36 are withdrawn.
Claims 26-29, and 37-39 are under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Rejections
Claim Rejections under 35 USC § 102
The rejection of claims 26-29, 37 and 39 under 35 U.S.C. 102(a)(1) as being anticipated by Isaacson et al (Experimental Eye Research, 2018), as evidenced by Advanced BioMatrix product data sheet is withdrawn in light of the submitted affidavit/declaration.
Claim Rejections under 35 USC § 103
The rejection of claim 38 under 35 U.S.C. 103 as being unpatentable over Isaacson et al (Experimental Eye Research, 2018), in view of Echalier et al ( Material Today, 2017) is withdrawn in light of the submitted affidavit/declaration.
New Ground of Rejection
Claim Rejections - 35 USC § 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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 26-29, 37 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al ( Biofabrication , 2019) in view of Isaacson et al (Experimental Eye Research, 2018).
Regarding claim 26-29, Kim et al disclose a 3D bioprinting method for producing artificial corneal stromal equivalents with the same thickness and transparency as recited in the instant claims. The method of Kim et al involves bioprinting human corneal keratocytes encapsulated in bioink comprising of bovine decellularized corneal-derived extracellular matrix (CodECM), which comprises of extracellular matrix proteins. It should be noted that ECM in Kim corneal stromal equivalent is obtained from a species different from the stromal cells (e.g. human cells and bovine extracellular matrix). This reads on step (a) and (b)(i) of claim 26 and claims 27-29. ( See section 2.1. “Preparation of bioink”). Kim et al further teach corneal constructs having a thickness of 200 µm, thereby meeting the claimed minimum thickness of 50 um. ( See section 2.6. “ Optical Transparency”). Kim et al also demonstrate that the corneal constructs are highly transparent with transmittance greater than the claimed minimum value of 0.5.( See Figure.4i). Taken together, Kim et al teach a corneal construct comprising of stromal cells from a first species (i.e. human) and extracellular matrix proteins from a second species (i.e. bovine), wherein the corneal construct having the claimed thickness and optical transmittance.
Kim et al, however, does not expressly disclose that the tissue is strongly curved or has a curvature of 0.04- 0.5 mm-1.
Isaacson et al supplement Kim et al by teaching the fabrication of an artificial corneal stromal equivalent formed on a curved support to produce the native corneal construct having the claimed curvature as recited in instant claim e.g. 0.04- 0.5 mm-1. Specifically, the method of Isaacson et al involves bioprinting corneal keratocytes encapsulated in composite bioink comprising of natural alginate and methacrylated type I collagen. Isaacson et al’s method also involves employing a support structure with an anatomically fabricated corneal scaffold that closely resembles human corneal anatomy to generate curved corneal stromal equivalents. (See Fig.1 F, and sections “2.1.” and “3.1. Isaacson et al further explain that the printed corneal constructs were generated using a support structure with a corneal scaffold, which has a horizontal diameter of 12.385 mm. In the drawing section of instant disclosure, a scaffold with 12mm diameter has a curvature (k) of 0.16. (See the table incorporated in Fig.1 of instant disclosure). Therefore, Isaacson et al’s method generates corneal constructs with 0.16 mm-1, which falls within the recited numerical range of 0.04 to about 0.5 mm-1. (See section 2.1.). Therefore, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to modify the corneal construct of Kim et al by fabricating the construct with the curved geometry taught by Issacson. Because Isaacson et al teach that reproducing the native corneal curvature provides corneal stromal equivalent that is suitable for corneal tissue engineering. Therefore, an ordinary skill in the art would be motivated to apply the known curved geometry of Issacson to the transparent and appropriately thick corneal stromal construct of Kim to produce a curved corneal stromal equivalent replicating the native corneal anatomy. In other words, claim 26 is combining prior art elements according to known methods to yield predictable results, namely the predictable result being the production of corneal stromal equivalent with the claimed structural and functional properties.
Regarding claims 37 and 39, the method of Kim et al involves encapsulating the human keratocytes in hydrogel comprising of decellularized ECM , which is composed of extracellular matrix proteins containing natural cell adhesion motif, and wherein the ECM is extracted from bovine (i.e. second species).
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Kim et al in view of Isaacson et al as applied to claim 26-29, 37 and 39 above, and further in view of Echalier et al ( Material Today, 2017).
The teachings of Kim et al and Isaacson et al are set forth above. Kim in view of Isaacson et al render obvious claims 26-29, 37 and 39.
Regarding claim 38, neither Kim nor Isaacson et al teach encapsulating stromal cells in hydrogel comprising synthetic adhesion motif.
Echalier et al demonstrate how to prepare fully synthetic hydrogel that mimics collagen by utilizing a peptide derived from a common collagen repeat (Pro-Hyp-Gly). The method of Echalier et al also involves chemically modifying the peptide so that it can undergo a sol-gel process in a physiological buffer, allowing for the embedding of stem cell in the matrix. Echalier et al demonstrate that the resulting hydrogel provides an environment comparable to the natural collagen in terms of cell growth, making it potentially useful as a biomimetic scaffold for bioprinting and tissue engineering applications. (See abstract, conclusion, and Figs.4-5). Echalier et al state that “the natural polymers are usually costly, they encounter low batch-to-batch reproducibility, microbial contaminants during the isolation process and potential immunogenicity in the case of animal extracts” and propose the use of the synthetic hydrogels to overcome such issues. Therefore, claim 38 would have been obvious to one of ordinary skill in the art at the time the invention was filed, as there was 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. Kim et al used 3D bioprinting to create artificial corneal stromal equivalents by encapsulating corneal keratocytes in composite bioink comprising of natural decellularized ECM while Isaacson et al relied upon a mix of methacrylated collagen and sodium alginate. Echalier et al demonstrate how to make fully synthetic hydrogel capable of providing an environment comparable to the natural ECM in terms of cell growth, and directly suggest that synthetic hydrogels could be useful as a biomimetic scaffold for bioprinting and tissue engineering applications. Therefore, there is a reasonable expectation of success in replacing the natural hydrogel comprising of natural extracellular matrix proteins, such as collagen, with a synthetic hydrogel comprised of synthetic collagen peptides, because doing so would avoid the purification problems associated with the extraction of natural biopolymers.
Response to Arguments
Applicant's arguments filed 04/22/2026 have been fully considered but they are not persuasive.
Applicants argue that the methods of Isaacson et al. produce a corneal stromal equivalent having lower transmittance of visible light compared to the stromal cell tissues of the invention.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully
considered, but are not found fully persuasive. While applicant’s arguments are peruasive for the 102 rejection over Isaacson et al., the new ground of rejection does not rely on Isaacson for teaching the claimed transmittance. Rather, Kim et al are relied upon for teaching an engineered corneal stromal equivalent exhibiting the claimed optical transmittance, while Isaacson et al are relied upon for teaching the fabrication of corneal stromal equivalent having the claimed curvature. ( See rejection above).
Applicants further argue that Echalier et al. merely demonstrates basic adhesion and proliferation of stem cells, which does not guarantee the maintenance of corneal-specific function, and thus a skilled person would not expect hydrogels comprising the synthetic [Pro-Hyp-Gly ]3 motif to possess the specific refractive index or ultrastructural organization required for a corneal substitute, nor assume it to provide a suitable niche for the maintenance of corneal stromal cells with their specific phenotype.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully
considered, but are not found persuasive. This is because the rejection does not rely on Echalier et al. to teach a corneal stromal construct having the claimed optical properties, including visible light transmittance, nor is Echalier relied upon to teach maintenance of corneal-specific stromal cell phenotype. Rather, Kim et al. are relied upon for teaching an engineered corneal stromal tissue having the claimed thickness and optical transmittance, and Isaacson et al. are relied upon for teaching the claimed curved corneal construct. Echalier et al. are relied upon solely for teaching that synthetic extracellular matrix protein sequences may be used as biomimetic scaffolds for cell encapsulation in tissue engineering.
Echalier teaches that synthetic extracellular matrix protein sequences are designed to mimic the biological functions of native extracellular matrix and provide suitable environments for cell adhesion, proliferation, differentiation, and tissue engineering while offering advantages such as reproducibility. One of ordinary skill in the art would have found it obvious to substitute the naturally derived extracellular matrix of Kim with the synthetic extracellular matrix protein sequence taught by Echalier because both materials serve the same known purpose of providing an extracellular matrix scaffold for encapsulating cells in engineered tissues. Such substitution represents the predictable use of one known scaffold material for another to obtain the recognized advantages of synthetic extracellular matrix materials.
Applicant’s contention that Echalier does not demonstrate corneal-specific function, refractive index, or ultrastructural organization is unpersuasive because the rejection does not rely on Echalier for those teachings. The rejection relies on the combined teachings of Kim, Isaacson, and Echalier, and nonobviousness cannot be established by attacking references individually where the rejection is based upon their combined disclosures. See In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights