DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on 01/28/2026 has been entered.
Claims 1-17, 19-20 and 62 are pending in this application.
Applicant’s amendment to the claims filed 01/28/2026 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s remarks filed on 01/28/2026 in response to the final rejection mailed on 10/08/2025 are acknowledged and have been fully considered.
The rejections to claim 18 are withdrawn in view of the cancelation of the claim.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election
The elected subject matter is
Group I, corresponding to claims 1-17, 19-20 and 62, drawn to the technical feature of a method of forming a scaffold from donor corneal stroma excised from a central region of a donor corneal source comprising: decellularizing donor corneal stroma to obtain a scaffold; removing fluid present in the scaffold; and crosslinking at least a portion of the scaffold to inhibit subsequent swelling,
elected without traverse in the reply filed 09/20/2024.
Claims 1-17, 19-20 and 62 are being examined on the merits.
Claim Rejections - 35 USC § 112(b)
The rejection of claims 1-20 and 62 under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention are withdrawn in view of the instant claim amendments, particularly the amendment to claim 1 to recite no longer recite the relative term “sufficient”, and in view of Applicant’s persuasive remarks.
Claims 1-7, 19-20 and 62 are newly rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The instant rejection is necessitated by claim amendment.
Claim 1 (claims 2-17, 19-20 and 62 dependent therefrom) is rejected for the recitation of “implanting … a … lenticule exhibiting … optical clarity”. The examiner has reviewed the specification and can find no definition of the phrase “optical clarity” and it is unclear from the specification and prior art of record as to the intended meaning of “optical clarity.” As the specification indicates optical clarity to be a quantifiable characteristic [para 0064], and the claims do not limit any specific degree of optical clarity, the scope of the claim is considered to be indefinite.
Response to Remarks: beginning on page 6 of Applicant’s response to rejections under 35 USC 112(b); Applicant in summary contends the amendments to the claims overcome the rejections of record.
Applicant’s remarks are considered and found not convincing, as there are new grounds of rejection raised in view of the claim amendments.
Claim Rejections - 35 USC § 112(a)
Claims 1-17, 19-20 and 62 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. This is a new matter rejection and is necessitated by amendment.
The instant rejection is maintained from the previous office action where it was directed to the claim 1 limitation of “decellularized corneal lenticule exhibiting sufficient optical clarity for use in intrastromal implantation”, and any newly recited portions are necessitated by the instant amendment to claim 1 to incorporate the subject matter of canceled claim 18.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims.” See also MPEP 714.02. MPEP § 2163.II.A.3.(b) further states, “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, para. 1, as lacking adequate written description.” According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.”
Claim 1 (claims 2-17, 19-20 and 62 dependent therefrom) has been amended to recite “a decellularized corneal lenticule exhibiting a scattering angle of less than 4 arcminutes and optical clarity for use in intrastromal implantation”. Applicant has not stated where any support for the instant amendment can be found in the instant application, and there is no apparent descriptive support for the limitation “a decellularized corneal lenticule exhibiting a scattering angle of less than 4 arcminutes and optical clarity for use in intrastromal implantation” in the original application as filed. Applicant is invited to show support for the limitation at issue.
Claim Rejections - 35 USC § 103
The rejections set forth in the previous Office action (pp. 7-29) under 35 USC 103 are withdrawn in view of the amendment to claim 1 to recite “a scattering angle of less than 4 arcminutes”.
Claims 1, 3-6, 8-9, 15, 19-20 and 62 are newly rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (Curr Eye Res, 2016, 41:769; cited on the IDS filed 12/14/2023; herein referred to as Wilson) in view of Cumming et al. (US 4,793,344; cited on the IDS filed 12/11/2020; herein referred to as Cumming), Soker et al. (US 2010/0215717; cited on the IDS filed 10/20/2021; herein referred to as Soker) and Knox et al. (US 2012 0310223; cited on the IDS filed 10/20/2021; herein referred to as Knox).
The instant rejection is newly stated and necessitated by claim amendment.
Claim 1 is drawn to a method of correcting a visual error, comprising:
implanting, in a patient's stromal bed, a decellularized corneal lenticule exhibiting a scattering angle of less than 4 arcminutes and optical clarity for use in intrastromal implantation and comprising a scaffold obtained from donor corneal stroma excised from a central region of a donor corneal source and exhibiting a collagen concentration of at least 20%,
wherein the collagen concentration of the scaffold is measured as a fractional weight of the scaffold in a desiccated state relative to the weight of the scaffold in a state in full equilibrium with water,
wherein at least a portion of the scaffold is crosslinked to inhibit subsequent swelling thereof.
Wilson discusses methods of decellularizing human corneal tissues [abstract].
Regarding the limitation in claim 1 of a decellularized donor corneal lenticule obtained from a donor corneal stroma excised from a central region of a donor corneal source, Wilson teaches a method of decellularizing human cornea, wherein the corneas are human tissue from donors [p 770, col 1, paras 4-5], and wherein the decellularized cornea is subsequently characterized and used as a scaffold on which corneal stroma cells are grown [p 772, col 1, paras 1-3]. As the decellularization method of Wilson additionally includes the removal of epithelium and endothelium [p 770, col 1, para 5], it is considered to encompass the excision of stroma from a central region of a donor corneal source.
Regarding the limitation in claim 1 of correcting a visual error comprising implanting, in a patient’s stromal bed, a decellularized corneal lenticule exhibiting optical clarity for use in intrastromal implantation, Wilson teaches the transplantation of corneas to treat corneal blindness implicitly through the disclosure of the number of rejected corneal transplantations of harvested corneas due to the failure of said transplants to meet biological screening criteria, and the suggestion that this rate could be improved through increased research into the use of decellularized human tissue [p 769, col 1, para 1, to p 770, col 1, para 3] which is the focus of the body of the reference. Wilson’s method of decellularization is considered to produce a decellularized corneal lenticule based on the definition of a lenticule in the instant specification of “a decellularized, processed donor corneal tissue ready for implantation into or onto a recipient's cornea” [para 0075]. As Wilson discusses the preparation of decellularized corneal lenticules from human tissue to overcome transplant deficiencies known in the field to correct corneal blindness, the transplant of said lenticule is understood to occur in the stromal bed, and is considered to correspond to a lenticule exhibiting optical clarity for use in intrastromal implantation.
Regarding swelling, Wilson teaches the inclusion of some hypotonic solutions during nuclease treatments of the prepared scaffold caused structural disruption, wherein the hypotonic solutions caused the cells in the scaffold to swell [p 778, col 2, para 1].
Wilson does not teach crosslinking at least a portion of the scaffold to inhibit subsequent swelling, a scaffold of at least 20% collagen measured as a fractional weight of desiccated vs. equilibrated in water, and a scattering angle of less than 4 arcminutes.
Cumming discusses a method for preparing corneal donor tissue for refractive eye surgery [title] and describes methods that produce lenticules of predictable lens power and prevent immunological for subsequent eye surgery including corneal transplants.
Regarding the limitation in claim 1 of crosslinking at least a portion of the scaffold to inhibit subsequent swelling, Cumming teaches a method of creating a bank of donor tissues with pre-established refractive powers that can be conveniently selected and used for refractive eye surgery, wherein donor tissue is treated with a fixative agent such as glutaraldehyde to neutralize the immune response as well as crosslink the tissue to prevent swelling and enable long-term storage without deterioration [col 2, ln 7-16].
Soker discusses endothelial scaffolds [title] consisting of decellularized corneal stroma for treating patients in need of a corneal endothelial transplant [abstract].
Regarding claim 1 and the limitation of at least 20% collagen in the scaffold, Soker teaches a method of producing a scaffold of decellularized stromal tissue that has a collagen component of between 50-90, or 60-80% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea [para 0037]. Soker further teaches the decellularized stroma maintains similar mechanical behavior to native corneal stroma [para 0042]. Regarding collagen, Soker teaches transparency is a consequence of the detailed ultrastructure of the tissue and has been attributed to the narrow, uniform diameter of collagen fibrils, and to the regularity of their lateral packing [para 0038]. Therefore Soker identifies collagen content and structure to be a result effective variable according to MPEP 2144.05.II.B, which is a variable that achieves a recognized result. While Soker does not teach a scaffold comprising at least 20% collagen measured as fractional weight of the desiccated scaffold compared to a fully hydrated scaffold as recited in the claims, Soker teaches a method of producing a scaffold of decellularized stromal tissue with a collagen component between 50-90% dry weight of the decellularized scaffold as stated above, wherein the corneal stroma itself is isolated from tissue comprised of 90% or more stroma (by weight) and of 10% or less non-stroma tissue [para 0023], wherein the stroma is indicated to contain the collagen [para 0024]. Additionally, Soker teaches that the stromal tissue can be sectioned prior to or after decellularizing [para 0037]. The teachings of Soker therefore identify multiple ways of altering the collagen content of the scaffold.
According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. As Soker teaches a method of producing a scaffold of decellularized stromal tissue that has a collagen component of between 50-90% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea as well as multiple methods for varying stromal content and therefore collagen content, one of ordinary skill in the art would have been capable of achieving the claimed collagen % because Soker teaches multiple methods of altering collagen content in a scaffold, and one of ordinary skill in the art would have been motivated to alter collagen content because Soker teaches that collagen content and structure is a result effective variable that alters transparency.
Knox discusses a method for modifying the refractive index (RI) of ocular tissues [title], and describes methods using a laser to modify the RI of ocular tissues such as the corneal stroma for correcting and/or optimizing vision [para 0003].
Regarding claim 1 and the limitation of the lenticule scattering angle, Knox teaches it is of interest to write structures that have low scattering and high optical quality for ophthalmic applications [para 0146]. Knox further teaches to correct higher-order aberrations in addition to minimizing the effects of “rainbow”, which is a diffraction-based effect, wherein structures with reduction of line spacing from 1 micron to 0.7-0.5 microns show reduced rainbow effects [para 0152]. As such, Knox teaches a method of altering corneal stroma in order to optimize vision and correct higher-order aberrations related to light scattering and diffraction.
In view of Wilson, Cumming, and Soker, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Wilson by crosslinking the decellularized scaffold, as taught by Cumming, and modify the % collagen component as taught by Soker, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the method of Wilson by crosslinking the scaffold tissue, because Wilson teaches some hypotonic solutions used in the method of preparing a lenticule cause structural disruption due to swelling, and Cumming teaches the use of glutaraldehyde to crosslink the tissue and prevent swelling. One of ordinary skill in the art would have been motivated to modify the % collagen because Soker teaches the use of a decellularized stroma with specific amounts of collagen that maintain similar mechanical behavior to native corneal stroma, and teaches methods to alter the amount of collagen in a scaffold as well as that collagen content and structure is a result effective variable that alters transparency. One of ordinary skill in the art would have had a reasonable expectation of success because Wilson, Cumming and Soker relate to methods of preparing corneal tissue for transplant.
In view of Knox, it would have been it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Wilson, Cumming, and Soker by correcting aberrations by writing structures with low scattering, as taught by Knox, to arrive at the claimed invention by routine optimization. According to MPEP 2144.05.II, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. One of ordinary skill in the art would have been motivated to modify the combined method of Wilson, Cumming, and Soker by correcting aberrations through writing structures with low scattering, because Knox teaches correcting ocular tissues such as corneal stroma to optimize vision by minimizing or reducing scattering. One of ordinary skill in the art would have had a reasonable expectation of success because Cumming and Knox relate to methods of modifying corneal tissue for improved visual function
Regarding claim 3, Cumming teaches the shaping of the one or both surfaces of the lenticule with an oblative laser [col 3, ln 26-29].
Regarding claim 4, Cummings teaches the method vacuum-lathing to shape the tissue as an alternative to the use of an ablative laser [col 3, ln 26-29], which is considered to correspond to the introduction of the scaffold to a vacuum that would have the effect of removing at least a portion of the fluid from the scaffold as recited in the claim.
Regarding claim 5, Wilson teaches decellularization commonly uses detergents and hypertonic solutions [p 770, col 1, para 4], which correspond to the use of a chemical decellularizing agent.
Regarding claim 6, Wilson teaches the initial decellularization using a hypertonic solution of 1.5 M NaCl in PBS, 0.5% (w/v) SDS in PBS or 1% (w/v) Triton-X100, followed by the washing of corneas with PBS [p 770, col 2, para 4], which is considered to correspond to the removal of cell debris with a detergent or a surfactant.
Regarding claim 8, Soker teaches the method of producing an endothelial scaffold of decellularized stromal tissue that has a collagen component of between 50-90, or 60-80% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea [para 0037], which is understood to have a greater concentration of collagen as the scaffold contains the disclosed amount of collagen but without the associated cells of the excised donor corneal stroma, and therefore the scaffold is interpreted to have the naturally occurring amount of collagen with the reduced mass afforded by the decellularized stroma.
Regarding claim 9, Soker teaches a method of producing a scaffold of decellularized stromal tissue that has a collagen component of between 50-90% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea [para 0037], teaches methods of altering stroma content and therefore collagen content [paras 0023-0024, 0037], and teaches collagen content and structure is a result effective variable according to MPEP 2144.05.II.B that alters transparency [para 0038] as discussed in the rejection of claim 1 above. While Soker does not teach a scaffold comprising the % collagen recited in the claim as measured as fractional weight of the desiccated scaffold compared to a fully hydrated scaffold, MPEP 2144.05.II.A states where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore one of ordinary skill in the art would have been capable of achieving the claimed collagen % because Soker teaches multiple methods of altering collagen content in a scaffold, and one of ordinary skill in the art would have been motivated to alter collagen content because Soker teaches that collagen content and structure is a result effective variable that alters transparency.
Regarding claim 15, Cumming teaches a method of producing a lenticule with a known shape comprising lathing the tissue to provide a selected shape and thickness [claim 1] that can be further shaped with an eximer laser [claim 10]. As the produced lenticule is to be used for transplantation in an eye surgery [abstract], it is understood to comprise a body, an anterior surface and a posterior surface.
Regarding claims 19-20, the teachings of Knox related to correcting ocular tissues to optimize vision by minimizing or reducing scattering are discussed in the rejection of claim 1 above. While Knox does not teach the scattering angles of less than 3 or less than 2 arcminutes (claim 19), or the scattering angle of less than 1 arcminute (claim 20), MPEP 2144.05.II.A states where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore one of ordinary skill in the art would have been motivated to minimize the scattering angle as taught by Knox to arrive at the claimed invention because Knox teaches such minimization corrects ocular tissues such as corneal stroma to optimize vision.
Regarding claim 62, Wilson teaches the transplantation of corneas to treat corneal blindness implicitly through the disclosure of the number of rejected corneal transplantations of harvested corneas due to the failure of said transplants to meet biological screening criteria, and the suggestion that this rate could be improved through increased research into the use of decellularized human tissue [p 769, col 1, para 1, to p 770, col 1, para 3], wherein corneal blindness is considered to be an ocular condition.
Therefore, the invention of claims 1, 3-6, 8-9, 15, 19-20 and 62 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 2 is newly rejected under 35 U.S.C. 103 as being unpatentable over Wilson in view of Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 above, and further in view of Moshirfar et al. (J Cataract Refract Surg, 2015, 41:652; cited on the Form PTO-892 mailed 01/23/2025; herein referred to as Moshirfar).
The instant rejection is newly stated and necessitated by claim amendment.
Claim 2 is drawn to the method of claim 1, wherein the scaffold is formed by performing a lenticular extraction on a cornea with a keratome, laser, or water jet to obtain donor corneal stroma.
The teachings of Wilson, Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 are described above. These references do not teach a lenticular extraction on a cornea with a keratome, laser, or water jet.
Moshirfar reviews small-incision lenticule extraction [title], and discusses procedures for extracting lenticules such as small incision lenticule extraction, femtosecond lenticule extraction, and laser in situ keratomileusis [abstract].
Regarding claim 2, Moshirfar teaches the procedure of small-incision lenticule extraction is a type of femtosecond laser-based technique that is a less invasive alternative to LASIK for the correction of myopic error [p 652, col 2, para 1], wherein the lenticule is extracted in the process depicted in [Figure 4].
In view of Moshirfar, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Wilson, Cumming, Soker and Knox by using a laser for the lenticule extraction, as taught by Moshirfar, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of Wilson, Cumming, Soker and Knox by using a laser for lenticule extraction, because Moshirfar teaches small-incision lenticule extraction is a type of femtosecond laser-based technique that is a less invasive alternative to LASIK for the correction of myopic error. One of ordinary skill in the art would have had a reasonable expectation of success because Wilson and Moshirfar relate to methods of performing lenticule extraction.
Therefore, the invention of claim 2 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 7 is newly rejected under 35 U.S.C. 103 as being unpatentable over Wilson in view of Cumming, Soker, Knox and Moshirfar as applied to claims 1-6, 8-9, 15, 19-20 and 62 above, and further in view of Xu et al. (US 2015 0126453; cited on the IDS filed 05/26/2023; herein referred to as Xu).
The instant rejection is newly stated and necessitated by claim amendment.
Claim 7 is drawn to the method of claim 2, wherein the scaffold is further formed by enzymatically removing or conformationally altering at least one immunogenic epitope of the scaffold.
The teachings of Wilson, Cumming, Soker, Knox and Moshirfar as applied to claims 1-6, 8-9, 15, 19-20 and 62 are described above. These references do not teach enzymatically removing or conformationally altering an epitope of the scaffold.
Xu discusses immunogenic epitope such as galactose alpha-1,3 galactose [title] and describes methods of preparing tissue matrices that lack some or all of such epitope [para 0001].
Regarding claim 7, Xu teaches a problem with transplantation from xenograft sources is the expression of foreign proteins that heighten the possibility for rejection, such as galactose alpha-1,3-galactose or “alpha-gal” that can cause an increased immune response and hyperacute rejection of xenografts from animals [para 0003]. Xu therefore teaches a method for removing the epitope alpha-gal from a collagen-containing decellularized tissue matrix [para 0004] by exposing the tissue, prior to transplantation, to a protease such as alcalase, bromelain, trypsin, or dispase [para 0026].
In view of Xu, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Wilson, Cumming, Soker, Knox and Moshirfar by enzymatically removing an immunogenic epitope from the scaffold, as taught by Xu, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of Wilson, Cumming, Soker, Knox and Moshirfar by using an enzymatic treatment, because Xu teaches the removal of immunogenic epitopes such alpha-gal via enzymes can decrease the possibility of transplant rejection. One of ordinary skill in the art would have had a reasonable expectation of success because Wilson and Xu relate to methods of preparing decellularized tissue for transplant.
Therefore, the invention of claim 7 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 10-11 and 16 are newly rejected under 35 U.S.C. 103 as being unpatentable over Wilson in view of Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 above, and further in view of Sun et al. (US 2012 0010728; cited on the IDS filed 12/11/2020; herein referred to as Sun) and Davidenko et al. (J Mater Sci Mater Med, 2016, 27:14; cited on the Form PTO-892 mailed 10/08/2025; herein referred to as Davidenko).
The instant rejection is newly stated and necessitated by claim amendment.
Claim 10 is drawn to the method of claim 1, wherein said at least portion of the scaffold that is crosslinked is generated via compressing said scaffold and exposing at least a portion of the compressed scaffold to actinic radiation.
Claim 11 is drawn to the method of claim 10, wherein the step of exposing at least a portion of the compressed scaffold to the actinic radiation induces crosslinking by peptide bond formation between collagen fibrils without the assistance of a crosslinking promoter or other energy mediating agent and optionally wherein the actinic radiation comprises any of ultraviolet radiation, x-rays, gamma radiation or an electron beam.
Claim 16 is drawn to the method of claim 10, wherein the step of cross-linking further comprises treating at least a portion of the posterior surface of the decellularized corneal lenticule with a crosslinking agent or by selective applications of patterning radiation to promote adherence of the decellularized corneal lenticule to the patient’s stromal bed.
The teachings of Wilson, Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 are described above. These references do not teach said at least portion of the scaffold that is crosslinked is generated via compressing said scaffold and exposing at least a portion of the compressed scaffold to actinic radiation.
Sun discusses methods for shaping tissue matrices [title], and discusses that in order to treat certain tissue or organ defects it may be desirable to form predefined shapes or configurations that more closely conform to anatomic structures to be treated [para 0004].
Regarding claim 10 and the limitation of compressing the scaffold and exposing a portion of the scaffold to radiation, Sun teaches a method of shaping a collagen-containing tissue matrix comprising dehydrating the matrix and applying mechanical forces to change the orientation of the collagen fibers, and exposing the tissue matrix to radiation [para 0005], wherein the radiation can result in cross-linking to produce a stable three dimensional structure [para 0042], and wherein the dehydration step comprises blot-drying with sterile GAMMA WIPES to both remove water from the tissue matrix as well as apply mechanical pressure, e.g. compression, to the matrix to reorient the collagen fibers [para 0052]. On the topic of cross-linking, Cumming teaches the treatment of the scaffold with glutaraldehyde in order to cross-link the tissue and prevent swelling [col 2, ln 7-16]. Neither Cumming nor Sun teach cross-linking the collagen in the scaffold with actinic radiation.
Regarding claim 10, the term “actinic radiation” is understood in the art to refer to UV irradiation with sufficient energy to cause photochemical reactions, and the specification at [para 0147] discloses that UV radiation is an example of actinic crosslinking radiation.
Davidenko relates to the optimization of UV irradiation as a binding site conserving method for crosslinking collagen-based scaffolds [title], and regarding claim 10, teaches methods of exposing collagen scaffolds to UV irradiation to provide a low level of cross-linking of collagen without loss of biological activity [abstract].
In view of Sun and Davidenko, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Wilson, Cumming, Soker and Knox by compressing the scaffold, as taught by Sun, and cross-linking the scaffold with UV radiation, as taught by Davidenko, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of Wilson, Cumming, Soker and Knox by compressing the scaffold, because Sun teaches it is desirable to shape collagen-containing tissue matrices by applying mechanical forces such as compression to form predefined shapes or configurations that more closely conform to anatomic structures in order to treat certain tissue or organ defects. One of ordinary skill in the art would have been motivated to modify the combined method of Wilson, Cumming, Soker and Knox by cross-linking the scaffold with UV radiation, because Cummings teaches the cross-linking of scaffolds to prevent tissue swelling, and Davidenko teaches treating collagen scaffolds to UV irradiation to provide a low level of cross-linking of collagen without loss of biological activity. One of ordinary skill in the art would have had a reasonable expectation of success because Wilson and Sun relate to methods of preparing tissue for transplant, and Cummings, Sun and Davidenko relate to cross-linking collagen scaffolds.
Regarding claim 11, Davidenko teaches methods of exposing collagen scaffolds to UV irradiation to provide a low level of cross-linking of collagen without loss of biological activity [abstract], which is understood to induce peptide bond formation between fibrils, and is carried out without the assistance of a cross-linking promoter [p 13, col 2, sections 2.2-2.3].
Regarding claim 16 and the phrase “treating at least a portion of the posterior surface of the decellularized corneal lenticule with a crosslinking agent or by selective application of patterning radiation to promote adherence of the decellularized corneal lenticule to the patient’s stromal bed”, the limitations of “with a crosslinking agent” and “by selective application of patterning radiation to promote adherence of the decellularized corneal lenticule to the patient’s stromal bed” are interpreted as alternatives in view of the linking of the two phrases with the conjunction “or”.
Regarding claim 16 in view of the interpretation set forth above, Cumming teaches the treatment of the tissue with a crosslinking agent to prevent swelling [col 2, ln 7-16]. As the treatment comprises “placing the tissue in a fixative solution” [claim 1], the crosslinking is considered to contact the entire surface of the tissue, and therefore is considered to encompasses treating at least a portion of the posterior surface as recited in the claim.
Therefore, the invention of claims 10-11 and 16 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 12 is newly rejected under 35 U.S.C. 103 as being unpatentable over Wilson in view of Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 above, and further in view of O’Brart et al. (J Optom, 2014, 7:113; cited on the Form PTO-892 mailed 01/23/2025; herein referred to as OBrart).
The instant rejection is newly stated and necessitated by claim amendment.
Claim 12 is drawn to the method of claim 10, wherein the step of crosslinking further comprises exposing at least a portion of the compressed scaffold to ultraviolet radiation by direct exposure, or by exposure at a grazing incidence angle or via an evanescent waveguide coupled to a surface of the scaffold.
The teachings of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. These references do not teach exposing at least a portion of the compressed scaffold to ultraviolet radiation.
OBrart reviews corneal crosslinking [title], and discusses the use of riboflavin/ultraviolet A (UVA) corneal collagen crosslinking (CXL) is the first treatment modality to halt the progression of keratoconus and other corneal ectatic disorders with improvement in visual, keratometric and topographic parameters [abstract].
Regarding claim 12, OBrart teaches current CXL techniques comprise UVA energies of 3 mW/cm2 and require 30 min of UVA exposure [p 118, col 2, para 1], which is considered to encompass direct exposure.
In view of OBrart, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Wilson, Cumming, Soker, Knox, Sun and Davidenko by using UVA to crosslink the collagen scaffold, as taught by OBrart, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of Wilson, Cumming, Soker, Knox, Sun and Davidenko by using UVA, because OBrart teaches riboflavin/ultraviolet A (UVA) corneal collagen crosslinking is the first treatment modality to halt the progression of keratoconus and other corneal ectatic disorders with improvement in visual, keratometric and topographic parameters. One of ordinary skill in the art would have had a reasonable expectation of success because Cummings and Sun relate to methods of crosslinking collagen tissue, and Sun and OBrart relate to methods of using radiation to crosslink collagen tissue.
Therefore, the invention of claim 12 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 13 is newly rejected under 35 U.S.C. 103 as being unpatentable over Wilson in view of Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 above, and further in view of Morishige et al. (Invest Ophthalmol Vis Sci, 2011, 52:911; cited on the IDS submitted 10/20/2021; herein referred to as Morishige).
The instant rejection is newly stated and necessitated by claim amendment.
Claim 13 is drawn to the method of claim 10, wherein the step of crosslinking further comprises selectively exposing a portion of the compressed scaffold to a radiation such that the surface portion of the exhibits greater crosslinking and higher collagen density than a bulk region of the scaffold.
The teachings of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. These references do not teach selectively exposing a portion of the compressed scaffold to a radiation such that the surface portion of the exhibits greater crosslinking and higher collagen density than a bulk region of the scaffold.
Morishige discusses the three-dimensional analysis of collagen lamellae in the anterior stroma of the human cornea [title].
Regarding claim 13, Morishige teaches the collagen lamellae in the anterior stroma of human cornea are highly organized, well interwoven, and densely packed, contributing to maintenance of the 3D structure of the anterior stroma [p 914, col 1, para 1]. As Cummings teaches that crosslinking stabilizes the structure of the scaffold as discussed above, and Sun teaches the use of radiation to crosslink scaffolds produces stable three dimensional structure as discussed above, one of skill in the art would be motivated to focus radiation on the anterior stroma in order to further impart structural stability, as Morishige teaches this densely packed area contributes to the maintenance of the 3D structure itself.
In view of Morishige, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Wilson, Cumming, Soker, Knox, Sun and Davidenko by focusing the crosslinking radiation to the anterior stroma to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of Wilson, Cumming, Soker, Knox, Sun and Davidenko by focusing the crosslinking radiation to the anterior stroma to increase the structural stability of the scaffold, because Cummings and Sun teach the use of crosslinking to stabilize the structure of corneal scaffolds, and Morishige teaches the densely packed anterior stroma further contributes to the maintenance of the 3D structure itself. One of ordinary skill in the art would have had a reasonable expectation of success because Sun relates to the crosslinking of collagen in corneal stroma using radiation, and Morishige relates to the 3D architecture of the corneal stroma.
Therefore, the invention of claim 13 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 14 is newly rejected under 35 U.S.C. 103 as being unpatentable over Wilson in view of Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 above, and further in view of Guangzhou Sun Shing Biotech et al. (CN 107233143; cited on the Form PTO-892 mailed 01/23/2025; reference is made to a machine translation; herein referred to as GSSB).
The instant rejection is newly stated and necessitated by claim amendment.
Claim 14 is drawn to the method of claim 10, wherein the step of crosslinking further comprises applying sufficient radiation to inactivate any microbial agents and/or sterilize the scaffold.
The teachings of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. These references do not teach applying sufficient radiation to inactivate any microbial agents and/or sterilize the scaffold.
GSSB discusses methods for preparation of corneal stroma lens [title], and describes a method of producing a corneal stroma lens to reduce its immunogenicity [abstract].
Regarding claim 14, GSSB teaches a method of producing a corneal stroma lens comprising removing the corneal lens, crosslinking [claim 1] and sterilization via irradiation with gamma rays [claim 9].
In view of GSSB, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Wilson, Cumming, Soker, Knox, Sun and Davidenko by sterilizing the scaffold with radiation, as taught by GSSB, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of Wilson, Cumming, Soker, Knox, Sun and Davidenko by sterilizing the scaffold with radiation, because GSSB teaches the use of gamma rays to irradiate and sterilize corneal stroma lenses to reduce their immunogenicity. One of ordinary skill in the art would have had a reasonable expectation of success because Wilson, Cummings and GSSB relate to methods of producing corneal stroma lenticules.
Therefore, the invention of claim 14 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 17 is newly rejected under 35 U.S.C. 103 as being unpatentable over Wilson in view of Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 above, and further in view of Dahl et al. (Optometry, 2012, 83:33; cited on the Form PTO-892 mailed 01/23/2025; herein referred to as Dahl).
The instant rejection is newly stated and necessitated by claim amendment.
Claim 17 is drawn to the method of claim 10, wherein the step of cross-linking further comprises enhancing the optical clarity of the scaffold.
The teachings of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. These references do not teach the step of cross-linking further comprises enhancing the optical clarity of the scaffold.
Dahl reviews corneal collagen crosslinking (CXL) [title], and discusses that CXL shows stabilization or improvement in best-corrected visual acuity, uncorrected visual acuity, and spherical and cylinder refractive measurements [abstract].
Regarding claim 17, Dahl teaches that because corneal transparency is essential for proper function, and corneal fibril arrangement and spacing are essential in maintaining said transparency, collagen fibril diameter as a result of CXL cannot exceed one third the wavelength of visible light in order to maintain clarity (p 37, col 2, para 3], wherein corneal transparency is understood to be related to optical clarity.
In view of Dahl, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Wilson, Cumming, Soker, Knox, Sun and Davidenko by following the guidelines regarding the arrangement and spacing of corneal fibrils upon CXL to affect transparency, as taught by Dahl, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of Wilson, Cumming, Soker, Knox, Sun and Davidenko by following the guidelines affecting transparency, because Dahl teaches that CXL shows stabilization or improvement in best-corrected visual acuity, uncorrected visual acuity, and spherical and cylinder refractive measurements given that one follows said guidelines. One of ordinary skill in the art would have had a reasonable expectation of success because Cumming and Dahl relate to methods of crosslinking corneal tissue.
Therefore, the invention of claim 17 would have been obvious to one of ordinary skill in the art before the effective filing date.
Response to Remarks: beginning on page 7 of Applicant’s response to rejections under 35 USC 103; Applicant in summary contends Wilson teaches away from forming a lenticule suitable for corneal implantation due to a significant reduction in transparency; Applicant further contends Cumming and Soker do not solve said transparency problem; Applicant further contends there is no reason to look into Soker to modify the scaffolds of Wilson and/or Cummings, and there is no teaching or suggestion how to render a decellularized corneal lenticule transparent so that it can be used for implantation in a subject’s stromal layer; Applicant further contends Soker’s teaching of % collagen corresponds to dry weight which is distinguished from the fractional weight requirements of the claim; Applicant further contends it is not clear whether the combination of the teachings of Knox would reduce or increase problems in scattering, and thus there would be no reasonable expectation of success in combining Knox with any of the prior art of record.
Applicants remarks are considered and found not convincing.
Regarding the assertion that Wilson teaches away from forming a lenticule suitable for corneal implantation, Wilson does not teach away from this technique as Wilson does not criticize, discredit, or otherwise discourage carrying out the forming lenticules suitable for corneal transplantation (see MPEP 2143.01.I). Additionally, Wilson teaches the transplantation of corneas to treat corneal blindness implicitly through the disclosure of the number of rejected corneal transplantations of harvested corneas due to the failure of said transplants to meet biological screening criteria, and the suggestion that this rate could be improved through increased research into the use of decellularized human tissue. Wilson additionally discloses a method of decellularization to address this problem, therefore suggesting the use of said decellularized human tissue in transplants.
Regarding the assertion that Cumming and Soker do not solve the transparency problem of Wilson, Cumming and Soker are brought in to address features of claim 1 corresponding to inhibiting scaffold swelling and to use a decellularized scaffold comprising particular amounts of collagen, respectively. As stated in the rejection under 112(b) above, the claims require a lenticule to have optical clarity, but do not specify any quantifiable amount of clarity, and therefore the claims encompass any amount of optical clarity in the method as recited in claim 1. Furthermore, as Wilson discusses the preparation of decellularized corneal lenticules from human tissue to overcome transplant deficiencies known in the field to correct corneal blindness, the transplant is considered to correspond to a lenticule exhibiting optical clarity for use in intrastromal implantation.
Regarding the assertion that there is no reason to look into Soker to modify the scaffolds of Wilson and/or Cummings, and there is no teaching or suggestion how to render a decellularized corneal lenticule transparent so that it can be used for implantation in a subject’s stromal layer, the claims do not require the lenticule to be transparent. The claims recite the lenticule must have optical clarity, but as stated above the claims do not specify any quantifiable amount of clarity or transparency, and therefore the claims encompass any amount of optical clarity in the method as recited in claim 1.
Regarding the assertion that Soker’s teaching of % collagen corresponds to dry weight which is distinguished from the fractional weight requirements of the claim, as stated in the rejection above, Soker identifies collagen content and structure to be a result effective variable according to MPEP 2144.05.II.B, and teaches a method of forming a scaffold of decellularized stromal tissue with a collagen component between 50-90% dry weight of the decellularized scaffold, as well as multiple ways of altering the collagen content of the scaffold. While Soker does not disclose the % collagen according to the measurement recited in the claims, MPEP 2144.05.II.A states where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation, and one of ordinary skill in the art would have been capable of achieving the claimed collagen % because Soker teaches methods that would alter the collagen content of a scaffold, and one of skill in the art would have been motivated to alter the collagen content of the scaffold because Soker identifies collagen content and structure as a result effective variable which alters transparency.
Regarding the assertion that it is not clear whether the combination of the teachings of Knox would reduce or increase problems in scattering, and thus there would be no reasonable expectation of success in combining Knox with any of the prior art of record: Knox discusses a method for modifying the refractive index of ocular tissues for correcting and/or optimizing vision, and teaches to write structures that have low scattering and high optical quality for ophthalmic applications. Therefore Knox directly teaches the minimization of scattering. Additionally, there is no indication that teachings of Knox would be incapable of reducing the scattering of a lenticule as asserted by Applicant, and the claims do not require any specific method to achieve the recited scattering angle. One of ordinary skill in the art would have a reasonable expectation of success in carrying out the combined method of Wilson, Cummings and Soker with a lenticule having a scattering angle of less than 4 arcminutes because Knox teaches the benefits of minimizing scattering in structures for ophthalmic applications.
Double Patenting
The double patenting rejections set forth in the previous Office action labeled under heading B. (pp. 37-57) are withdrawn in view of the instant claim amendment to claim 1 to recite “a scattering angle of less than 4 arcminutes”.
A. Claims 1, 3-17, 19-20 and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-16 of U.S. Patent No. 12,350,144 (cited on the Form PTO-892 mailed 10/08/2025; herein “patent”) in view of Wilson.
The instant rejection is maintained from a previous office action, and any newly recited portion is necessitated by claim amendment.
Regarding instant claim 1, claim 1 of the patent recites a method of forming a scaffold from donor corneal stroma excised from a central region of a donor corneal source comprising decellularizing donor corneal stroma to obtain a scaffold, removing at least a portion of fluid present in the scaffold to form a compacted scaffold exhibiting a collagen concentration of at least 20% for intrastromal implantation, crosslinking at least a portion of the scaffold, and wherein the scaffold exhibits sufficient optical clarity for use in intrastromal implantation, and claim 15 of the patent recites the scaffold exhibits a scattering angle, theta, of less than 4 arcminutes.
The claims of the patent do not recite a method for correcting visual error comprising the scaffold recited in the instant.
Wilson discusses methods of decellularizing human corneal tissues [abstract].
Regarding the limitation in claim 1 of a decellularized donor corneal lenticule obtained from a donor corneal stroma excised from a central region of a donor corneal source, Wilson discloses a method of decellularizing human cornea, wherein the corneas are human tissue from donors [p 770, col 1, paras 4-5], and wherein the decellularized cornea is subsequently characterized and used as a scaffold on which corneal stroma cells are grown [p 772, col 1, paras 1-3]. As the decellularization method of Wilson additionally includes the removal of epithelium and endothelium [p 770, col 1, para 5], it is considered to encompass the excision of stroma from a central region of a donor corneal source.
Regarding the limitation in claim 1 of correcting a visual error comprising implanting, in a patient’s stromal bed, a decellularized corneal lenticule exhibiting sufficient optical clarity for use in intrastromal implantation, Wilson discloses the transplantation of corneas to treat corneal blindness implicitly through the disclosure of the number of rejected corneal transplantations of harvested corneas due to the failure of said transplants to meet biological screening criteria, and the suggestion that this rate could be improved through increased research into the use of decellularized human tissue [p 769, col 1, para 1, to p 770, col 1, para 3] which is the focus of the body of the reference. Wilson’s method of decellularization is considered to produce a decellularized corneal lenticule based on the definition of a lenticule in the instant specification of “a decellularized, processed donor corneal tissue ready for implantation into or onto a recipient's cornea” [para 0075]. As Wilson discusses the preparation of decellularized corneal lenticules from human tissue to overcome transplant deficiencies known in the field to correct corneal blindness, the transplant of said lenticule is understood to occur in the stromal bed, and is considered to correspond to a lenticule exhibiting sufficient optical clarity for use in intrastromal implantation.
In view of Wilson, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the patent by correcting a visual error as disclosed by Wilson to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the claims of the patent by correcting a visual error, because Wilson discusses the preparation of decellularized corneal lenticules from human tissue to overcome transplant deficiencies known in the field to correct corneal blindness, and the patent recites the preparation of a corneal scaffold for intrastromal implantation. One of ordinary skill in the art would have had a reasonable expectation of success because the patent and Wilson relate to methods of preparing corneal tissue for transplant.
Regarding instant claim 3, claim 12 of the patent recites the scaffold is configured for use as an implantable lenticule having a lenticule body, an anterior surface and a posterior surface that give the lenticule a final desired shape.
Regarding instant claim 4, claim 1 of the patent recites the step of applying mechanical pressure on the scaffold to remove at least a portion of the fluid.
Regarding instant claim 5, claim 3 of the patent recites the step of decellularizing further comprises treating the scaffold with a chemical decellularizing agent and optionally wherein the step of decellularizing occurs before or after removing the fluid, or before or after crosslinking.
Regarding instant claim 6, claim 4 of the patent recites the step of decellularizing further comprises removing cellular debris from the scaffold with a detergent or a surfactant.
Regarding instant claim 7, claim 5 of the patent recites enzymatically removing or conformationally altering at least one immunogenic epitope of the scaffold.
Regarding instant claim 8, claim 6 of the patent recites the crosslinked scaffold exhibits a collagen concentration of at least 40 percent, and claim 1 of the patent recites the scaffold is formed through decellularization of a donor corneal stroma, therefore it is scaffold understood to have a greater concentration of collagen, as the scaffold contains the disclosed amount of collagen but without the associated cells of the donor corneal stroma, and therefore the scaffold is interpreted to have the naturally occurring amount of collagen with the reduced mass afforded by the decellularized stroma.
Regarding instant claim 9, claim 6 of the patent recites the crosslinked scaffold exhibits a collagen concentration of at least 40 percent.
Regarding instant claim 10, claim 7 of the patent recites exposing at least a portion of the compressed scaffold to a crosslinking promoter or actinic radiation.
Regarding instant claim 11, claim 8 of the patent recites exposing at least a portion of the compressed scaffold to radiation to induce crosslinking by peptide bond formation between collagen fibrils with or without the assistance of a crosslinking promoter or other energy mediating agent and optionally wherein the step of crosslinking the scaffold further comprises irradiating the scaffold with ultraviolet radiation, x-rays, gamma radiation or an electron beam.
Regarding instant claim 12, claim 9 of the patent recites exposing at least a portion of the compressed scaffold to ultraviolet radiation by direct exposure, or by exposure at a grazing incidence angle or via an evanescent waveguide coupled to a surface of the scaffold.
Regarding instant claim 13, claim 10 of the patent recites selectively exposing a surface portion of the compressed scaffold to a radiation such that the surface portion exhibits greater crosslinking and higher collagen density than a bulk region of the scaffold.
Regarding instant claim 14, claim 11 of the patent recites the step of crosslinking further comprises applying sufficient radiation to inactivate any microbial agents and/or sterilize the scaffold.
Regarding instant claim 15, claim 12 of the patent recites
the scaffold is configured for use as an implantable lenticule having a lenticule body, an anterior surface and a posterior surface that give the lenticule a final desired shape.
Regarding instant claim 16, claim 13 of the patent recites treating at least a portion of the posterior surface of the lenticule with a crosslinking agent or by selective application of patterning radiation to promote adherence of the lenticule to a stromal bed when implanted into a patient's stromal bed.
Regarding instant claim 17, claim 14 of the patent recites enhancing the optical clarity of the scaffold.
Regarding instant claim 19, claim 16 of the patent recites
he scaffold exhibits a scattering angle, theta, of less than 3 arcminutes or less than 2 arcminutes.
Regarding instant claim 20, claim 16 of the patent recites
he scaffold exhibits a scattering angle, theta, of less than 1 arcminutes.
Regarding instant claim 62, Wilson discloses the transplantation of corneas to treat corneal blindness implicitly through the disclosure of the number of rejected corneal transplantations of harvested corneas due to the failure of said transplants to meet biological screening criteria, and the suggestion that this rate could be improved through increased research into the use of decellularized human tissue [p 769, col 1, para 1, to p 770, col 1, para 3], wherein corneal blindness is considered to be an ocular condition.
Claim 2 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-16 of U.S. Patent No. 12,350,144 in view of Wilson as applied to claims 1, 3-17, 19-20 and 62 above, and further in view of Moshirfar.
The claims of the patent as applied to instant claims 1, 3-17, 19-20 and 62 are described above. The claims of the patent do not recite a lenticular extraction on a cornea with a keratome, laser, or water jet.
Moshirfar reviews small-incision lenticule extraction [title], and discusses procedures for extracting lenticules such as small incision lenticule extraction, femtosecond lenticule extraction, and laser in situ keratomileusis [abstract].
Regarding instant claim 2, Moshirfar discloses the procedure of small-incision lenticule extraction is a type of femtosecond laser-based technique that is a less invasive alternative to LASIK for the correction of myopic error [p 652, col 2, para 1], wherein the lenticule is extracted in the process depicted in [Figure 4].
In view of Moshirfar, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the patent by using a laser for the lenticule extraction, as disclosed by Moshirfar, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the claims of the patent by using a laser for lenticule extraction, because Moshirfar discloses small-incision lenticule extraction is a type of femtosecond laser-based technique that is a less invasive alternative to LASIK for the correction of myopic error. One of ordinary skill in the art would have had a reasonable expectation of success because the patent and Moshirfar relate to methods of performing lenticule extraction.
B. Claims 1, 3-6, 8-9, 15, 19-20 and 62 are newly rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,329,632 (cited on the Form PTO-892 mailed 10/08/2025; herein “patent”) in view of Wilson, Cumming, Soker, and Knox.
The instant rejection is necessitated by claim amendment.
Regarding instant claim 1, claim 1 of the patent recites a method for correcting an error in a subject's vision, comprising implanting an intrastromal decellularized corneal lenticule within corneal stromal region of the subject's cornea such that a posterior surface of the implanted lenticule is positioned on an intrastromal bed of the subject's cornea, wherein the corneal lenticule includes a lenticular body derived from donor corneal tissue having an anterior surface that includes a Bowman's membrane from the donor corneal tissue and a posterior surface that is shaped to provide the lenticule with a desired shape for correcting an error in vision upon intrastromal implantation.
The claims of the patent do not recite a scaffold obtained from donor corneal stroma excised from a central region of a donor corneal source, wherein the scaffold is formed by decellularizing donor corneal stroma to obtain the scaffold; the recited % collagen concentration of the scaffold; crosslinking at least a portion of the scaffold to inhibit subsequent swelling; and the scattering angle of the lenticule recited in the instant claim.
Wilson discusses methods of decellularizing human corneal tissues [abstract].
Regarding the limitation in instant claim 1 of a decellularized donor corneal lenticule obtained from a donor corneal stroma excised from a central region of a donor corneal source, Wilson discloses a method of decellularizing human cornea, wherein the corneas are human tissue from donors [p 770, col 1, paras 4-5], and wherein the decellularized cornea is subsequently characterized and used as a scaffold on which corneal stroma cells are grown [p 772, col 1, paras 1-3]. As the decellularization method of Wilson additionally includes the removal of epithelium and endothelium [p 770, col 1, para 5], it is considered to encompass the excision of stroma from a central region of a donor corneal source.
Regarding the limitation in instant claim 1 of correcting a visual error comprising implanting, in a patient’s stromal bed, a decellularized corneal lenticule exhibiting optical clarity for use in intrastromal implantation, Wilson discloses the transplantation of corneas to treat corneal blindness implicitly through the disclosure of the number of rejected corneal transplantations of harvested corneas due to the failure of said transplants to meet biological screening criteria, and the suggestion that this rate could be improved through increased research into the use of decellularized human tissue [p 769, col 1, para 1, to p 770, col 1, para 3] which is the focus of the body of the reference. Wilson’s method of decellularization is considered to produce a decellularized corneal lenticule based on the definition of a lenticule in the instant specification of “a decellularized, processed donor corneal tissue ready for implantation into or onto a recipient's cornea” [para 0075]. As Wilson discusses the preparation of decellularized corneal lenticules from human tissue to overcome transplant deficiencies known in the field to correct corneal blindness, the transplant of said lenticule is understood to occur in the stromal bed, and is considered to correspond to a lenticule exhibiting optical clarity for use in intrastromal implantation.
Regarding swelling, Wilson discloses the inclusion of some hypotonic solutions during nuclease treatments of the prepared scaffold caused structural disruption, wherein the hypotonic solutions caused the cells in the scaffold to swell [p 778, col 2, para 1].
Cumming discusses a method for preparing corneal donor tissue for refractive eye surgery [title] and describes methods that produce lenticules of predictable lens power and prevent immunological for subsequent eye surgery including corneal transplants.
Regarding the limitation in instant claim 1 of crosslinking at least a portion of the scaffold to inhibit subsequent swelling, Cumming discloses a method of creating a bank of donor tissues with pre-established refractive powers that can be conveniently selected and used for refractive eye surgery, wherein donor tissue is treated with a fixative agent such as glutaraldehyde to neutralize the immune response as well as crosslink the tissue to prevent swelling and enable long-term storage without deterioration [col 2, ln 7-16].
Soker discusses endothelial scaffolds [title] consisting of decellularized corneal stroma for treating patients in need of a corneal endothelial transplant [abstract].
Regarding instant claim 1 and the limitation of at least 20% collagen in the scaffold, Soker discloses a method of producing a scaffold of decellularized stromal tissue that has a collagen component of between 50-90, or 60-80% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea [para 0037]. Soker further discloses the decellularized stroma maintains similar mechanical behavior to native corneal stroma [para 0042]. Regarding collagen, Soker discloses the transparency is a consequence of the detailed ultrastructure of the tissue and has been attributed to the narrow, uniform diameter of collagen fibrils, and to the regularity of their lateral packing [para 0038]. Therefore Soker identifies collagen content and structure to be a result effective variable according to MPEP 2144.05.II.B, which is a variable that achieves a recognized result. While Soker does not disclose a scaffold comprising at least 20% collagen measured as fractional weight of the desiccated scaffold compared to a fully hydrated scaffold as recited in the claims, Soker discloses a method of producing a scaffold of decellularized stromal tissue with a collagen component between 50-90% dry weight of the decellularized scaffold as stated above, wherein the corneal stroma itself is isolated from tissue of at least 90% or more stroma (by weight) and 10% or less non-stroma tissue [para 0023], wherein the stroma is indicated to contain the collagen [para 0024]. Additionally, Soker discloses that the stromal tissue can be sectioned prior to or after decellularizing [para 0037]. The disclosure of Soker therefore identifies multiple ways of altering the collagen content of the scaffold.
According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. As Soker discloses a method of producing a scaffold of decellularized stromal tissue that has a collagen component of between 50-90% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea as well as multiple methods for varying stromal content and therefore collagen content, one of ordinary skill in the art would have been capable of achieving the claimed collagen % because Soker discloses multiple methods of altering collagen content in a scaffold, and one of ordinary skill in the art would have been motivated to alter collagen content because Soker discloses that collagen content and structure is a result effective variable that alters transparency.
Knox discusses a method for modifying the refractive index (RI) of ocular tissues [title], and describes methods using a laser to modify the RI of ocular tissues such as the corneal stroma for correcting and/or optimizing vision [para 0003].
Regarding instant claim 1 and the limitation of the lenticule scattering angle, Knox discloses it is of interest to write structures that have low scattering and high optical quality for ophthalmic applications [para 0146]. Knox further discloses to correct higher-order aberrations in addition to minimizing the effects of “rainbow”, which is a diffraction-based effect, wherein structures with reduction of line spacing from 1 micron to 0.7-0.5 microns show reduced rainbow effects [para 0152]. As such, Knox discloses a method of altering corneal stroma in order to optimize vision and correct higher-order aberrations related to light scattering and diffraction.
In view of Wilson, Cumming, and Soker, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the patent by preparing the scaffold as disclosed by Wilson and Cumming, and to modify the % collagen component as disclosed by Soker, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the claims of the patent by crosslinking the scaffold tissue, because Wilson discloses some hypotonic solutions used in the method of preparing a lenticule cause structural disruption due to swelling, and Cumming discloses the use of glutaraldehyde to crosslink the tissue and prevent swelling. One of ordinary skill in the art would have been motivated to modify the % collagen because Soker discloses the use of a decellularized stroma with specific amounts of collagen that maintain similar mechanical behavior to native corneal stroma, and discloses methods to alter the amount of collagen in a scaffold as well as that collagen content and structure is a result effective variable that alters transparency. One of ordinary skill in the art would have had a reasonable expectation of success because the patent, reference application, Wilson and Cumming relate to methods of correcting ocular deficiencies through implantation of decellularized corneal lenticules, and the patent and Soker relate to preparing decellularized corneal stroma.
In view of Knox, it would have been it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, Wilson, Cumming, and Soker by correcting aberrations by writing structures with low scattering, as disclosed by Knox, to arrive at the claimed invention by routine optimization. According to MPEP 2144.05.II, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, Wilson, Cumming, and Soker by correcting aberrations through writing structures with low scattering, because Knox discloses correcting ocular tissues such as corneal stroma to optimize vision by minimizing or reducing scattering. One of ordinary skill in the art would have had a reasonable expectation of success because Cumming and Knox relate to methods of modifying corneal tissue for improved visual function
Regarding instant claim 3, Cumming discloses the shaping of the one or both surfaces of the lenticule with an oblative laser [col 3, ln 26-29].
Regarding instant claim 4, Cummings discloses the method vacuum-lathing to shape the tissue as an alternative to the use of an ablative laser [col 3, ln 26-29], which is considered to correspond to the introduction of the scaffold to a vacuum that would have the effect of removing at least a portion of the fluid from the scaffold as recited in the claim.
Regarding instant claim 5, Wilson discloses decellularization commonly uses detergents and hypertonic solutions [p 770, col 1, para 4], which correspond to the use of a chemical decellularizing agent.
Regarding instant claim 6, Wilson discloses the initial decellularization using a hypertonic solution of 1.5 M NaCl in PBS, 0.5% (w/v) SDS in PBS or 1% (w/v) Triton-X100, followed by the washing of corneas with PBS [p 770, col 2, para 4], which is considered to correspond to the removal of cell debris with a detergent or a surfactant.
Regarding instant claim 8, Soker discloses the method of producing an endothelial scaffold of decellularized stromal tissue that has a collagen component of between 50-90, or 60-80% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea [para 0037], which is understood to have a greater concentration of collagen as the scaffold contains the disclosed amount of collagen but without the associated cells of the excised donor corneal stroma, and therefore the scaffold is interpreted to have the naturally occurring amount of collagen with the reduced mass afforded by the decellularized stroma.
Regarding instant claim 9, Soker discloses a method of producing a scaffold of decellularized stromal tissue that has a collagen component of between 50-90% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea [para 0037], discloses methods of altering stroma content and therefore collagen content [paras 0023-0024, 0037], and discloses collagen content and structure is a result effective variable according to MPEP 2144.05.II.B that alters transparency [para 0038] as discussed in the rejection of instant claim 1 above. While Soker does not discloses a scaffold comprising the % collagen recited in the claim as measured as fractional weight of the desiccated scaffold compared to a fully hydrated scaffold, MPEP 2144.05.II.A states where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore one of ordinary skill in the art would have been capable of achieving the claimed collagen % because Soker discloses multiple methods of altering collagen content in a scaffold, and one of ordinary skill in the art would have been motivated to alter collagen content because Soker discloses that collagen content and structure is a result effective variable that alters transparency.
Regarding instant claim 15, Cumming discloses a method of producing a lenticule with a known shape comprising lathing the tissue to provide a selected shape and thickness [claim 1] that can be further shaped with an eximer laser [claim 10]. As the produced lenticule is to be used for transplantation in an eye surgery [abstract], it is understood to comprise a body, an anterior surface and a posterior surface.
Regarding instant claims 19-20, the disclosure of Knox related to correcting ocular tissues to optimize vision by minimizing or reducing scattering are discussed in the rejection of claim 1 above. While Knox does not disclose the scattering angles of less than 3 or less than 2 arcminutes (instant claim 19), or the scattering angle of less than 1 arcminute (instant claim 20), MPEP 2144.05.II states where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore one of ordinary skill in the art would have been motivated to minimize the scattering angle as disclosed by Knox to arrive at the claimed invention because Knox discloses such minimization corrects ocular tissues such as corneal stroma to optimize vision.
Regarding instant claim 62, Wilson discloses the transplantation of corneas to treat corneal blindness implicitly through the disclosure of the number of rejected corneal transplantations of harvested corneas due to the failure of said transplants to meet biological screening criteria, and the suggestion that this rate could be improved through increased research into the use of decellularized human tissue [p 769, col 1, para 1, to p 770, col 1, para 3], wherein corneal blindness is considered to be an ocular condition.
Claim 2 is newly rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,329,632 in view of Wilson, Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62, and further in view of Moshirfar.
The instant rejection is necessitated by claim amendment.
The claims of the patent and disclosures of Wilson, Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 are described above. The claims of the patent do not recite a lenticular extraction on a cornea with a keratome, laser, or water jet.
Moshirfar reviews small-incision lenticule extraction [title], and discusses procedures for extracting lenticules such as small incision lenticule extraction, femtosecond lenticule extraction, and laser in situ keratomileusis [abstract].
Regarding instant claim 2, Moshirfar discloses the procedure of small-incision lenticule extraction is a type of femtosecond laser-based technique that is a less invasive alternative to LASIK for the correction of myopic error [p 652, col 2, para 1], wherein the lenticule is extracted in the process depicted in [Figure 4].
In view of Moshirfar, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, Wilson, Cumming, Soker and Knox by using a laser for the lenticule extraction, as disclosed by Moshirfar, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, Wilson, Cumming, Soker and Knox by using a laser for lenticule extraction, because Moshirfar discloses small-incision lenticule extraction is a type of femtosecond laser-based technique that is a less invasive alternative to LASIK for the correction of myopic error. One of ordinary skill in the art would have had a reasonable expectation of success because the patent, Wilson and Moshirfar relate to methods of performing lenticule extraction.
Claim 7 is newly rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,329,632 in view of Wilson, Cumming, Soker, Knox and Moshirfar as applied to claims 1-2, 3-6, 8-9, 15, 19-20 and 62 above, and further in view of Xu.
The instant rejection is necessitated by claim amendment.
The claims of the patent and disclosures of Wilson, Cumming, Soker, Knox and Moshirfar as applied to claims 1-2, 3-6, 8-9, 15, 19-20 and 62 are described above. The claims of the patent do not recite enzymatically removing or conformationally altering an epitope of the scaffold.
Xu discusses immunogenic epitope such as galactose alpha-1,3 galactose [title] and describes methods of preparing tissue matrices that lack some or all of such epitope [para 0001].
Regarding instant claim 7, Xu discloses a problem with transplantation from xenograft sources is the expression of foreign proteins that heighten the possibility for rejection, such as galactose alpha-1,3-galactose or “alpha-gal” that can cause an increased immune response and hyperacute rejection of xenografts from animals [para 0003]. Xu therefore discloses a method for removing the epitope alpha-gal from a collagen-containing decellularized tissue matrix [para 0004] by exposing the tissue, prior to transplantation, to a protease such as alcalase, bromelain, trypsin, or dispase [para 0026].
In view of Xu, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, Wilson, Cumming, Soker, Knox and Moshirfar by enzymatically removing an immunogenic epitope from the scaffold, as disclosed by Xu, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, Wilson, Cumming, Soker, Knox and Moshirfar by using an enzymatic treatment, because Xu discloses the removal of immunogenic epitopes such alpha-gal via enzymes can decrease the possibility of transplant rejection. One of ordinary skill in the art would have had a reasonable expectation of success because the patent, Wilson and Xu relate to methods of preparing decellularized tissue for transplant.
Claims 10-11 and 16 are newly rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,329,632 in view of Wilson, Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 above, and further in view of Sun and Davidenko.
The instant rejection is necessitated by claim amendment.
The claims of the patent and disclosures of Wilson, Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 are described above. The claims of the patent do not recite said at least portion of the scaffold that is crosslinked is generated via compressing said scaffold and exposing at least a portion of the compressed scaffold to actinic radiation.
Sun discusses methods for shaping tissue matrices [title], and discusses that in order to treat certain tissue or organ defects it may be desirable to form predefined shapes or configurations that more closely conform to anatomic structures to be treated [para 0004].
Regarding instant claim 10 and the limitation of compressing the scaffold and exposing a portion of the scaffold to radiation, Sun discloses a method of shaping a collagen-containing tissue matrix comprising dehydrating the matrix and applying mechanical forces to change the orientation of the collagen fibers, and exposing the tissue matrix to radiation [para 0005], wherein the radiation can result in cross-linking to produce a stable three dimensional structure [para 0042], and wherein the dehydration step comprises blot-drying with sterile GAMMA WIPES to both remove water from the tissue matrix as well as apply mechanical pressure, e.g. compression, to the matrix to reorient the collagen fibers [para 0052]. On the topic of cross-linking, Cumming discloses the treatment of the scaffold with glutaraldehyde in order to cross-link the tissue and prevent swelling [col 2, ln 7-16]. Neither Cumming nor Sun disclose cross-linking the collagen in the scaffold with actinic radiation.
Regarding claim 10, the term “actinic radiation” is understood in the art to refer to UV irradiation with sufficient energy to cause photochemical reactions, and the specification at [para 0147] discloses that UV radiation is an example of actinic crosslinking radiation.
Davidenko relates to the optimization of UV irradiation as a binding site conserving method for crosslinking collagen-based scaffolds [title], and regarding instant claim 10, discloses methods of exposing collagen scaffolds to UV irradiation to provide a low level of cross-linking of collagen without loss of biological activity [abstract].
In view of Sun and Davidenko, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, Wilson, Cumming, Soker and Knox by compressing the scaffold, as disclosed by Sun, and cross-linking the scaffold with UV radiation, as disclosed by Davidenko, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, Wilson, Cumming, Soker and Knox by compressing the scaffold, because Sun discloses it is desirable to shape collagen-containing tissue matrices by applying mechanical forces such as compression to form predefined shapes or configurations that more closely conform to anatomic structures in order to treat certain tissue or organ defects. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, Wilson, Cumming, Soker and Knox by cross-linking the scaffold with UV radiation, because Cummings discloses the cross-linking of scaffolds to prevent tissue swelling, and Davidenko discloses treating collagen scaffolds to UV irradiation to provide a low level of cross-linking of collagen without loss of biological activity. One of ordinary skill in the art would have had a reasonable expectation of success because the patent, Wilson and Sun relate to methods of preparing tissue for transplant, and Cummings, Sun and Davidenko relate to cross-linking collagen scaffolds.
Regarding instant claim 11, Davidenko discloses methods of exposing collagen scaffolds to UV irradiation to provide a low level of cross-linking of collagen without loss of biological activity [abstract], which is understood to induce peptide bond formation between fibrils, and is carried out without the assistance of a cross-linking promoter [p 13, col 2, sections 2.2-2.3].
Regarding instant claim 16 and the phrase “treating at least a portion of the posterior surface of the decellularized corneal lenticule with a crosslinking agent or by selective application of patterning radiation to promote adherence of the decellularized corneal lenticule to the patient’s stromal bed”, the limitations of “with a crosslinking agent” and “by selective application of patterning radiation to promote adherence of the decellularized corneal lenticule to the patient’s stromal bed” are interpreted as alternatives in view of the linking of the two phrases with the conjunction “or”.
Regarding instant claim 16 in view of the interpretation set forth above, Cumming discloses the treatment of the tissue with a crosslinking agent to prevent swelling [col 2, ln 7-16]. As the treatment comprises “placing the tissue in a fixative solution” [claim 1], the crosslinking is considered to contact the entire surface of the tissue, and therefore is considered to encompasses treating at least a portion of the posterior surface as recited in the claim.
Claim 12 is newly rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,329,632 in view of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 18-19 and 62 above, and further in view of OBrart.
The instant rejection is necessitated by claim amendment.
The claims of the patent and disclosures of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. The claims of the patent do not recite exposing at least a portion of the compressed scaffold to ultraviolet radiation.
OBrart reviews corneal crosslinking [title], and discusses the use of riboflavin/ultraviolet A (UVA) corneal collagen crosslinking (CXL) is the first treatment modality to halt the progression of keratoconus and other corneal ectatic disorders with improvement in visual, keratometric and topographic parameters [abstract].
Regarding instant claim 12, OBrart discloses current CXL techniques comprise UVA energies of 3 mW/cm2 and require 30 min of UVA exposure [p 118, col 2, para 1], which is considered to encompass direct exposure.
In view of OBrart, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, Wilson, Cumming, Soker, Knox, Sun and Davidenko by using UVA to crosslink the collagen scaffold, as disclosed by OBrart, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, Wilson, Cumming, Soker, Knox, Sun and Davidenko by using UVA, because OBrart discloses riboflavin/ultraviolet A (UVA) corneal collagen crosslinking is the first treatment modality to halt the progression of keratoconus and other corneal ectatic disorders with improvement in visual, keratometric and topographic parameters. One of ordinary skill in the art would have had a reasonable expectation of success because the patent, Cummings and Sun relate to methods of crosslinking collagen tissue, and Sun and OBrart relate to methods of using radiation to crosslink collagen tissue.
Claim 13 is newly rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,329,632 in view of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 above, and further in view of Morishige.
The instant rejection is necessitated by claim amendment.
The claims of the patent and disclosures Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. The claims of the patent do not recite selectively exposing a portion of the compressed scaffold to a radiation such that the surface portion of the exhibits greater crosslinking and higher collagen density than a bulk region of the scaffold.
Morishige discusses the three-dimensional analysis of collagen lamellae in the anterior stroma of the human cornea [title].
Regarding instant claim 13, Morishige discloses the collagen lamellae in the anterior stroma of human cornea are highly organized, well interwoven, and densely packed, contributing to maintenance of the 3D structure of the anterior stroma [p 914, col 1, para 1]. As Cummings discloses that crosslinking stabilizes the structure of the scaffold as discussed above, and Sun discloses the use of radiation to crosslink scaffolds produces stable three dimensional structure as discussed above, one of skill in the art would be motivated to focus radiation on the anterior stroma in order to further impart structural stability, as Morishige discloses this densely packed area contributes to the maintenance of the 3D structure itself.
In view of Morishige, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, Wilson, Cumming, Soker, Knox, Sun and Davidenko by focusing the crosslinking radiation to the anterior stroma to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, Wilson, Cumming, Soker, Knox, Sun and Davidenko by focusing the crosslinking radiation to the anterior stroma to increase the structural stability of the scaffold, because Cummings and Sun disclose the use of crosslinking to stabilize the structure of corneal scaffolds, and Morishige discloses the densely packed anterior stroma further contributes to the maintenance of the 3D structure itself. One of ordinary skill in the art would have had a reasonable expectation of success because the patent and Sun relate to crosslinking collagen in corneal stroma, Sun relates to the crosslinking of collagen in corneal stroma using radiation, and Morishige relates to the 3D architecture of the corneal stroma.
Claim 14 is newly rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,329,632 in view of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 above, and further in view of GSSB.
The instant rejection is necessitated by claim amendment.
The claims of the patent and disclosures of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. The claims of the patent do not recite applying sufficient radiation to inactivate any microbial agents and/or sterilize the scaffold.
GSSB discusses methods for preparation of corneal stroma lens [title], and describes a method of producing a corneal stroma lens to reduce its immunogenicity [abstract].
Regarding instant claim 14, GSSB discloses a method of producing a corneal stroma lens comprising removing the corneal lens, crosslinking [claim 1] and sterilization via irradiation with gamma rays [claim 9].
In view of GSSB, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, Wilson, Cumming, Soker, Knox, Sun and Davidenko by sterilizing the scaffold with radiation, as disclosed by GSSB, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, Wilson, Cumming, Soker, Knox, Sun and Davidenko by sterilizing the scaffold with radiation, because GSSB discloses the use of gamma rays to irradiate and sterilize corneal stroma lenses to reduce their immunogenicity. One of ordinary skill in the art would have had a reasonable expectation of success because the patent, Wilson, Cummings and GSSB relate to methods of producing corneal stroma lenticules.
Claim 17 is newly rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,329,632 in view of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 above, and further in view of Dahl.
The instant rejection is necessitated by claim amendment.
The claims of the patent and disclosures of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. The claims of the patent do not recite the step of cross-linking further comprises enhancing the optical clarity of the scaffold.
Dahl reviews corneal collagen crosslinking (CXL) [title], and discusses that CXL shows stabilization or improvement in best-corrected visual acuity, uncorrected visual acuity, and spherical and cylinder refractive measurements [abstract].
Regarding instant claim 17, Dahl discloses that because corneal transparency is essential for proper function, and corneal fibril arrangement and spacing are essential in maintaining said transparency, collagen fibril diameter as a result of CXL cannot exceed one third the wavelength of visible light in order to maintain clarity (p 37, col 2, para 3], wherein corneal transparency is understood to be related to optical clarity.
In view of Dahl, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the patent, Wilson, Cumming, Soker, Knox, Sun and Davidenko by following the guidelines regarding the arrangement and spacing of corneal fibrils upon CXL to affect transparency, as disclosed by Dahl, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the patent, Wilson, Cumming, Soker, Knox, Sun and Davidenko by following the guidelines affecting transparency, because Dahl discloses that CXL shows stabilization or improvement in best-corrected visual acuity, uncorrected visual acuity, and spherical and cylinder refractive measurements given that one follows said guidelines. One of ordinary skill in the art would have had a reasonable expectation of success because the patent, Cumming and Dahl relate to methods of crosslinking corneal tissue.
C. Claims 1, 3-6, 8-9, 15, 19-20 and 62 are newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/314,282 (herein “reference application”) in view of Wilson, Cumming, Soker, and Knox.
The instant rejection is necessitated by claim amendment.
Regarding instant claim 1, claim 1 of the reference application recites a collagenous lenticule for use in intrastromal implantation comprising a decellularized lenticular body derived from a corneal donor source.
The claims of the reference application do not recite a scaffold obtained from donor corneal stroma excised from a central region of a donor corneal source, wherein the scaffold is formed by decellularizing donor corneal stroma to obtain the scaffold; the recited % collagen concentration of the scaffold; crosslinking at least a portion of the scaffold to inhibit subsequent swelling; and the scattering angle of the lenticule recited in the instant claim.
Wilson discusses methods of decellularizing human corneal tissues [abstract].
Regarding the limitation in instant claim 1 of a decellularized donor corneal lenticule obtained from a donor corneal stroma excised from a central region of a donor corneal source, Wilson discloses a method of decellularizing human cornea, wherein the corneas are human tissue from donors [p 770, col 1, paras 4-5], and wherein the decellularized cornea is subsequently characterized and used as a scaffold on which corneal stroma cells are grown [p 772, col 1, paras 1-3]. As the decellularization method of Wilson additionally includes the removal of epithelium and endothelium [p 770, col 1, para 5], it is considered to encompass the excision of stroma from a central region of a donor corneal source.
Regarding the limitation in instant claim 1 of correcting a visual error comprising implanting, in a patient’s stromal bed, a decellularized corneal lenticule exhibiting optical clarity for use in intrastromal implantation, Wilson discloses the transplantation of corneas to treat corneal blindness implicitly through the disclosure of the number of rejected corneal transplantations of harvested corneas due to the failure of said transplants to meet biological screening criteria, and the suggestion that this rate could be improved through increased research into the use of decellularized human tissue [p 769, col 1, para 1, to p 770, col 1, para 3] which is the focus of the body of the reference. Wilson’s method of decellularization is considered to produce a decellularized corneal lenticule based on the definition of a lenticule in the instant specification of “a decellularized, processed donor corneal tissue ready for implantation into or onto a recipient's cornea” [para 0075]. As Wilson discusses the preparation of decellularized corneal lenticules from human tissue to overcome transplant deficiencies known in the field to correct corneal blindness, the transplant of said lenticule is understood to occur in the stromal bed, and is considered to correspond to a lenticule exhibiting optical clarity for use in intrastromal implantation.
Regarding swelling, Wilson discloses the inclusion of some hypotonic solutions during nuclease treatments of the prepared scaffold caused structural disruption, wherein the hypotonic solutions caused the cells in the scaffold to swell [p 778, col 2, para 1].
Cumming discusses a method for preparing corneal donor tissue for refractive eye surgery [title] and describes methods that produce lenticules of predictable lens power and prevent immunological for subsequent eye surgery including corneal transplants.
Regarding the limitation in instant claim 1 of crosslinking at least a portion of the scaffold to inhibit subsequent swelling, Cumming discloses a method of creating a bank of donor tissues with pre-established refractive powers that can be conveniently selected and used for refractive eye surgery, wherein donor tissue is treated with a fixative agent such as glutaraldehyde to neutralize the immune response as well as crosslink the tissue to prevent swelling and enable long-term storage without deterioration [col 2, ln 7-16].
Soker discusses endothelial scaffolds [title] consisting of decellularized corneal stroma for treating patients in need of a corneal endothelial transplant [abstract].
Regarding instant claim 1 and the limitation of at least 20% collagen in the scaffold, Soker discloses a method of producing a scaffold of decellularized stromal tissue that has a collagen component of between 50-90, or 60-80% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea [para 0037]. Soker further discloses the decellularized stroma maintains similar mechanical behavior to native corneal stroma [para 0042]. Regarding collagen, Soker discloses the transparency is a consequence of the detailed ultrastructure of the tissue and has been attributed to the narrow, uniform diameter of collagen fibrils, and to the regularity of their lateral packing [para 0038]. Therefore Soker identifies collagen content and structure to be a result effective variable according to MPEP 2144.05.II.B, which is a variable that achieves a recognized result. While Soker does not disclose a scaffold comprising at least 20% collagen measured as fractional weight of the desiccated scaffold compared to a fully hydrated scaffold as recited in the claims, Soker discloses a method of producing a scaffold of decellularized stromal tissue with a collagen component between 50-90% dry weight of the decellularized scaffold as stated above, wherein the corneal stroma itself is isolated from tissue of at least 90% or more stroma (by weight) and 10% or less non-stroma tissue [para 0023], wherein the stroma is indicated to contain the collagen [para 0024]. Additionally, Soker discloses that the stromal tissue can be sectioned prior to or after decellularizing [para 0037]. The disclosure of Soker therefore identifies multiple ways of altering the collagen content of the scaffold.
According to MPEP 2144.05.II.A, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. As Soker discloses a method of producing a scaffold of decellularized stromal tissue that has a collagen component of between 50-90% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea as well as multiple methods for varying stromal content and therefore collagen content, one of ordinary skill in the art would have been capable of achieving the claimed collagen % because Soker discloses multiple methods of altering collagen content in a scaffold, and one of ordinary skill in the art would have been motivated to alter collagen content because Soker discloses that collagen content and structure is a result effective variable that alters transparency.
Knox discusses a method for modifying the refractive index (RI) of ocular tissues [title], and describes methods using a laser to modify the RI of ocular tissues such as the corneal stroma for correcting and/or optimizing vision [para 0003].
Regarding instant claim 1 and the limitation of the lenticule scattering angle, Knox discloses it is of interest to write structures that have low scattering and high optical quality for ophthalmic applications [para 0146]. Knox further discloses to correct higher-order aberrations in addition to minimizing the effects of “rainbow”, which is a diffraction-based effect, wherein structures with reduction of line spacing from 1 micron to 0.7-0.5 microns show reduced rainbow effects [para 0152]. As such, Knox discloses a method of altering corneal stroma in order to optimize vision and correct higher-order aberrations related to light scattering and diffraction.
In view of Wilson, Cumming, and Soker, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the reference application by preparing the scaffold as disclosed by Wilson and Cumming, and to modify the % collagen component as disclosed by Soker, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the claims of the reference application by crosslinking the scaffold tissue, because Wilson discloses some hypotonic solutions used in the method of preparing a lenticule cause structural disruption due to swelling, and Cumming discloses the use of glutaraldehyde to crosslink the tissue and prevent swelling. One of ordinary skill in the art would have been motivated to modify the % collagen because Soker discloses the use of a decellularized stroma with specific amounts of collagen that maintain similar mechanical behavior to native corneal stroma, and discloses methods to alter the amount of collagen in a scaffold as well as that collagen content and structure is a result effective variable that alters transparency. One of ordinary skill in the art would have had a reasonable expectation of success because the reference application, Wilson and Cumming relate to methods of correcting ocular deficiencies through implantation of decellularized corneal lenticules, and the reference application and Soker relate to preparing decellularized corneal stroma.
In view of Knox, it would have been it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the reference application, Wilson, Cumming, and Soker by correcting aberrations by writing structures with low scattering, as disclosed by Knox, to arrive at the claimed invention by routine optimization. According to MPEP 2144.05.II, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. One of ordinary skill in the art would have been motivated to modify the combined method of the reference application, Wilson, Cumming, and Soker by correcting aberrations through writing structures with low scattering, because Knox discloses correcting ocular tissues such as corneal stroma to optimize vision by minimizing or reducing scattering. One of ordinary skill in the art would have had a reasonable expectation of success because Cumming and Knox relate to methods of modifying corneal tissue for improved visual function
Regarding instant claim 3, Cumming discloses the shaping of the one or both surfaces of the lenticule with an oblative laser [col 3, ln 26-29].
Regarding instant claim 4, Cummings discloses the method vacuum-lathing to shape the tissue as an alternative to the use of an ablative laser [col 3, ln 26-29], which is considered to correspond to the introduction of the scaffold to a vacuum that would have the effect of removing at least a portion of the fluid from the scaffold as recited in the claim.
Regarding instant claim 5, Wilson discloses decellularization commonly uses detergents and hypertonic solutions [p 770, col 1, para 4], which correspond to the use of a chemical decellularizing agent.
Regarding instant claim 6, Wilson discloses the initial decellularization using a hypertonic solution of 1.5 M NaCl in PBS, 0.5% (w/v) SDS in PBS or 1% (w/v) Triton-X100, followed by the washing of corneas with PBS [p 770, col 2, para 4], which is considered to correspond to the removal of cell debris with a detergent or a surfactant.
Regarding instant claim 8, Soker discloses the method of producing an endothelial scaffold of decellularized stromal tissue that has a collagen component of between 50-90, or 60-80% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea [para 0037], which is understood to have a greater concentration of collagen as the scaffold contains the disclosed amount of collagen but without the associated cells of the excised donor corneal stroma, and therefore the scaffold is interpreted to have the naturally occurring amount of collagen with the reduced mass afforded by the decellularized stroma.
Regarding instant claim 9, Soker discloses a method of producing a scaffold of decellularized stromal tissue that has a collagen component of between 50-90% dry weight of the decellularized scaffold in accordance with its natural occurrence in the cornea [para 0037], discloses methods of altering stroma content and therefore collagen content [paras 0023-0024, 0037], and discloses collagen content and structure is a result effective variable according to MPEP 2144.05.II.B that alters transparency [para 0038] as discussed in the rejection of instant claim 1 above. While Soker does not discloses a scaffold comprising the % collagen recited in the claim as measured as fractional weight of the desiccated scaffold compared to a fully hydrated scaffold, MPEP 2144.05.II.A states where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore one of ordinary skill in the art would have been capable of achieving the claimed collagen % because Soker discloses multiple methods of altering collagen content in a scaffold, and one of ordinary skill in the art would have been motivated to alter collagen content because Soker discloses that collagen content and structure is a result effective variable that alters transparency.
Regarding instant claim 15, Cumming discloses a method of producing a lenticule with a known shape comprising lathing the tissue to provide a selected shape and thickness [claim 1] that can be further shaped with an eximer laser [claim 10]. As the produced lenticule is to be used for transplantation in an eye surgery [abstract], it is understood to comprise a body, an anterior surface and a posterior surface.
Regarding instant claims 19-20, the disclosure of Knox related to correcting ocular tissues to optimize vision by minimizing or reducing scattering are discussed in the rejection of claim 1 above. While Knox does not disclose the scattering angles of less than 3 or less than 2 arcminutes (instant claim 19), or the scattering angle of less than 1 arcminute (instant claim 20), MPEP 2144.05.II states where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. Therefore one of ordinary skill in the art would have been motivated to minimize the scattering angle as disclosed by Knox to arrive at the claimed invention because Knox discloses such minimization corrects ocular tissues such as corneal stroma to optimize vision.
Regarding instant claim 62, Wilson discloses the transplantation of corneas to treat corneal blindness implicitly through the disclosure of the number of rejected corneal transplantations of harvested corneas due to the failure of said transplants to meet biological screening criteria, and the suggestion that this rate could be improved through increased research into the use of decellularized human tissue [p 769, col 1, para 1, to p 770, col 1, para 3], wherein corneal blindness is considered to be an ocular condition.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 2 is newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/314,282 in view of Wilson, Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 above, and further in view of Moshirfar.
The instant rejection is necessitated by claim amendment.
The claims of the reference application and disclosures of Wilson, Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 are described above. The claims of the reference application do not recite a lenticular extraction on a cornea with a keratome, laser, or water jet.
Moshirfar reviews small-incision lenticule extraction [title], and discusses procedures for extracting lenticules such as small incision lenticule extraction, femtosecond lenticule extraction, and laser in situ keratomileusis [abstract].
Regarding instant claim 2, Moshirfar discloses the procedure of small-incision lenticule extraction is a type of femtosecond laser-based technique that is a less invasive alternative to LASIK for the correction of myopic error [p 652, col 2, para 1], wherein the lenticule is extracted in the process depicted in [Figure 4].
In view of Moshirfar, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the reference application, Wilson, Cumming, Soker and Knox by using a laser for the lenticule extraction, as disclosed by Moshirfar, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the reference application, Wilson, Cumming, Soker and Knox by using a laser for lenticule extraction, because Moshirfar discloses small-incision lenticule extraction is a type of femtosecond laser-based technique that is a less invasive alternative to LASIK for the correction of myopic error. One of ordinary skill in the art would have had a reasonable expectation of success because the reference application, Wilson and Moshirfar relate to methods of performing lenticule extraction.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 7 is newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/314,282 in view of Wilson, Cumming, Soker, Knox and Moshirfar as applied to claims 1-2, 3-6, 8-9, 15, 19-20 and 62 above, and further in view of Xu.
The instant rejection is necessitated by claim amendment.
The claims of the reference application and disclosures of Wilson, Cumming, Soker, Knox and Moshirfar as applied to claims 1-2, 3-6, 8-9, 15, 19-20 and 62 are described above. The claims of the reference application do not recite enzymatically removing or conformationally altering an epitope of the scaffold.
Xu discusses immunogenic epitope such as galactose alpha-1,3 galactose [title] and describes methods of preparing tissue matrices that lack some or all of such epitope [para 0001].
Regarding instant claim 7, Xu discloses a problem with transplantation from xenograft sources is the expression of foreign proteins that heighten the possibility for rejection, such as galactose alpha-1,3-galactose or “alpha-gal” that can cause an increased immune response and hyperacute rejection of xenografts from animals [para 0003]. Xu therefore discloses a method for removing the epitope alpha-gal from a collagen-containing decellularized tissue matrix [para 0004] by exposing the tissue, prior to transplantation, to a protease such as alcalase, bromelain, trypsin, or dispase [para 0026].
In view of Xu, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the reference application, Wilson, Cumming, Soker, Knox and Moshirfar by enzymatically removing an immunogenic epitope from the scaffold, as disclosed by Xu, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the reference application, Wilson, Cumming, Soker, Knox and Moshirfar by using an enzymatic treatment, because Xu discloses the removal of immunogenic epitopes such alpha-gal via enzymes can decrease the possibility of transplant rejection. One of ordinary skill in the art would have had a reasonable expectation of success because the reference application, Wilson and Xu relate to methods of preparing decellularized tissue for transplant.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 10-11 and 16 are newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/314,282 in view of Wilson, Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 above, and further in view of Sun and Davidenko.
The instant rejection is necessitated by claim amendment.
The claims of the reference application and disclosures of Wilson, Cumming, Soker and Knox as applied to claims 1, 3-6, 8-9, 15, 19-20 and 62 are described above. The claims of the reference application do not recite said at least portion of the scaffold that is crosslinked is generated via compressing said scaffold and exposing at least a portion of the compressed scaffold to actinic radiation.
Sun discusses methods for shaping tissue matrices [title], and discusses that in order to treat certain tissue or organ defects it may be desirable to form predefined shapes or configurations that more closely conform to anatomic structures to be treated [para 0004].
Regarding instant claim 10 and the limitation of compressing the scaffold and exposing a portion of the scaffold to radiation, Sun discloses a method of shaping a collagen-containing tissue matrix comprising dehydrating the matrix and applying mechanical forces to change the orientation of the collagen fibers, and exposing the tissue matrix to radiation [para 0005], wherein the radiation can result in cross-linking to produce a stable three dimensional structure [para 0042], and wherein the dehydration step comprises blot-drying with sterile GAMMA WIPES to both remove water from the tissue matrix as well as apply mechanical pressure, e.g. compression, to the matrix to reorient the collagen fibers [para 0052]. On the topic of cross-linking, Cumming discloses the treatment of the scaffold with glutaraldehyde in order to cross-link the tissue and prevent swelling [col 2, ln 7-16]. Neither Cumming nor Sun disclose cross-linking the collagen in the scaffold with actinic radiation.
Regarding claim 10, the term “actinic radiation” is understood in the art to refer to UV irradiation with sufficient energy to cause photochemical reactions, and the specification at [para 0147] discloses that UV radiation is an example of actinic crosslinking radiation.
Davidenko relates to the optimization of UV irradiation as a binding site conserving method for crosslinking collagen-based scaffolds [title], and regarding instant claim 10, discloses methods of exposing collagen scaffolds to UV irradiation to provide a low level of cross-linking of collagen without loss of biological activity [abstract].
In view of Sun and Davidenko, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the reference application, Wilson, Cumming, Soker and Knox by compressing the scaffold, as disclosed by Sun, and cross-linking the scaffold with UV radiation, as disclosed by Davidenko, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the reference application, Wilson, Cumming, Soker and Knox by compressing the scaffold, because Sun discloses it is desirable to shape collagen-containing tissue matrices by applying mechanical forces such as compression to form predefined shapes or configurations that more closely conform to anatomic structures in order to treat certain tissue or organ defects. One of ordinary skill in the art would have been motivated to modify the combined method of the reference application, Wilson, Cumming, Soker and Knox by cross-linking the scaffold with UV radiation, because Cummings discloses the cross-linking of scaffolds to prevent tissue swelling, and Davidenko discloses treating collagen scaffolds to UV irradiation to provide a low level of cross-linking of collagen without loss of biological activity. One of ordinary skill in the art would have had a reasonable expectation of success because the reference application, Wilson and Sun relate to methods of preparing tissue for transplant, and Cummings, Sun and Davidenko relate to cross-linking collagen scaffolds.
Regarding instant claim 11, Davidenko discloses methods of exposing collagen scaffolds to UV irradiation to provide a low level of cross-linking of collagen without loss of biological activity [abstract], which is understood to induce peptide bond formation between fibrils, and is carried out without the assistance of a cross-linking promoter [p 13, col 2, sections 2.2-2.3].
Regarding instant claim 16 and the phrase “treating at least a portion of the posterior surface of the decellularized corneal lenticule with a crosslinking agent or by selective application of patterning radiation to promote adherence of the decellularized corneal lenticule to the patient’s stromal bed”, the limitations of “with a crosslinking agent” and “by selective application of patterning radiation to promote adherence of the decellularized corneal lenticule to the patient’s stromal bed” are interpreted as alternatives in view of the linking of the two phrases with the conjunction “or”.
Regarding instant claim 16 in view of the interpretation set forth above, Cumming discloses the treatment of the tissue with a crosslinking agent to prevent swelling [col 2, ln 7-16]. As the treatment comprises “placing the tissue in a fixative solution” [claim 1], the crosslinking is considered to contact the entire surface of the tissue, and therefore is considered to encompasses treating at least a portion of the posterior surface as recited in the claim.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 12 is newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/314,282 in view of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 18-19 and 62 above, and further in view of OBrart.
The instant rejection is necessitated by claim amendment.
The claims of the reference application and disclosures of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. The claims of the reference application do not recite exposing at least a portion of the compressed scaffold to ultraviolet radiation.
OBrart reviews corneal crosslinking [title], and discusses the use of riboflavin/ultraviolet A (UVA) corneal collagen crosslinking (CXL) is the first treatment modality to halt the progression of keratoconus and other corneal ectatic disorders with improvement in visual, keratometric and topographic parameters [abstract].
Regarding instant claim 12, OBrart discloses current CXL techniques comprise UVA energies of 3 mW/cm2 and require 30 min of UVA exposure [p 118, col 2, para 1], which is considered to encompass direct exposure.
In view of OBrart, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the reference application, Wilson, Cumming, Soker, Knox, Sun and Davidenko by using UVA to crosslink the collagen scaffold, as disclosed by OBrart, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the reference application, Wilson, Cumming, Soker, Knox, Sun and Davidenko by using UVA, because OBrart discloses riboflavin/ultraviolet A (UVA) corneal collagen crosslinking is the first treatment modality to halt the progression of keratoconus and other corneal ectatic disorders with improvement in visual, keratometric and topographic parameters. One of ordinary skill in the art would have had a reasonable expectation of success because Cummings and Sun relate to methods of crosslinking collagen tissue, and Sun and OBrart relate to methods of using radiation to crosslink collagen tissue.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 13 is newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/314,282 in view of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 above, and further in view of Morishige.
The instant rejection is necessitated by claim amendment.
The claims of the reference application and disclosures Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. The claims of the reference application do not recite selectively exposing a portion of the compressed scaffold to a radiation such that the surface portion of the exhibits greater crosslinking and higher collagen density than a bulk region of the scaffold.
Morishige discusses the three-dimensional analysis of collagen lamellae in the anterior stroma of the human cornea [title].
Regarding instant claim 13, Morishige discloses the collagen lamellae in the anterior stroma of human cornea are highly organized, well interwoven, and densely packed, contributing to maintenance of the 3D structure of the anterior stroma [p 914, col 1, para 1]. As Cummings discloses that crosslinking stabilizes the structure of the scaffold as discussed above, and Sun discloses the use of radiation to crosslink scaffolds produces stable three dimensional structure as discussed above, one of skill in the art would be motivated to focus radiation on the anterior stroma in order to further impart structural stability, as Morishige discloses this densely packed area contributes to the maintenance of the 3D structure itself.
In view of Morishige, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the reference application, Wilson, Cumming, Soker, Knox, Sun and Davidenko by focusing the crosslinking radiation to the anterior stroma to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the reference application, Wilson, Cumming, Soker, Knox, Sun and Davidenko by focusing the crosslinking radiation to the anterior stroma to increase the structural stability of the scaffold, because Cummings and Sun disclose the use of crosslinking to stabilize the structure of corneal scaffolds, and Morishige discloses the densely packed anterior stroma further contributes to the maintenance of the 3D structure itself. One of ordinary skill in the art would have had a reasonable expectation of success because Sun relates to the crosslinking of collagen in corneal stroma using radiation, and Morishige relates to the 3D architecture of the corneal stroma.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 14 is newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/314,282 in view of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 above, and further in view of GSSB.
The instant rejection is necessitated by claim amendment.
The claims of the reference application and disclosures of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. The claims of the reference application do not recite applying sufficient radiation to inactivate any microbial agents and/or sterilize the scaffold.
GSSB discusses methods for preparation of corneal stroma lens [title], and describes a method of producing a corneal stroma lens to reduce its immunogenicity [abstract].
Regarding instant claim 14, GSSB discloses a method of producing a corneal stroma lens comprising removing the corneal lens, crosslinking [claim 1] and sterilization via irradiation with gamma rays [claim 9].
In view of GSSB, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the reference application, Wilson, Cumming, Soker, Knox, Sun and Davidenko by sterilizing the scaffold with radiation, as disclosed by GSSB, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the reference application, Wilson, Cumming, Soker, Knox, Sun and Davidenko by sterilizing the scaffold with radiation, because GSSB discloses the use of gamma rays to irradiate and sterilize corneal stroma lenses to reduce their immunogenicity. One of ordinary skill in the art would have had a reasonable expectation of success because Wilson, Cummings and GSSB relate to methods of producing corneal stroma lenticules.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 17 is newly provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/314,282 in view of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 above, and further in view of Dahl.
The instant rejection is necessitated by claim amendment.
The claims of the reference application and disclosures of Wilson, Cumming, Soker, Knox, Sun and Davidenko as applied to claims 1, 3-6, 8-11, 15-16, 19-20 and 62 are described above. The claims of the reference application do not recite the step of cross-linking further comprises enhancing the optical clarity of the scaffold.
Dahl reviews corneal collagen crosslinking (CXL) [title], and discusses that CXL shows stabilization or improvement in best-corrected visual acuity, uncorrected visual acuity, and spherical and cylinder refractive measurements [abstract].
Regarding instant claim 17, Dahl discloses that because corneal transparency is essential for proper function, and corneal fibril arrangement and spacing are essential in maintaining said transparency, collagen fibril diameter as a result of CXL cannot exceed one third the wavelength of visible light in order to maintain clarity (p 37, col 2, para 3], wherein corneal transparency is understood to be related to optical clarity.
In view of Dahl, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of the reference application, Wilson, Cumming, Soker, Knox, Sun and Davidenko by following the guidelines regarding the arrangement and spacing of corneal fibrils upon CXL to affect transparency, as disclosed by Dahl, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of the reference application, Wilson, Cumming, Soker, Knox, Sun and Davidenko by following the guidelines affecting transparency, because Dahl discloses that CXL shows stabilization or improvement in best-corrected visual acuity, uncorrected visual acuity, and spherical and cylinder refractive measurements given that one follows said guidelines. One of ordinary skill in the art would have had a reasonable expectation of success because Cumming and Dahl relate to methods of crosslinking corneal tissue.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Remarks: beginning on page 16 of Applicant’s response to double patenting rejections; Applicant requests the rejections be deferred until the instant claims are allowable.
Applicant’s request is acknowledged and the rejections have been updated to reflect any claim amendments.
Conclusion
Status of the Application:
Claims 1-17, 19-20 and 62 are pending.
Claims 1-17, 19-20 and 62 are rejected.
No claim is in condition for allowance.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
Prosecution Insights