DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Applicants’ response of 9/29/2025 has been received and entered into the application file. Claims 1, 8-10, 12, 31, 32, 39-40, 57, 59, 61-66 and 69-75 are pending, all of which have been considered on the merits.
Status of Prior Rejections/Response to Arguments
RE: Claim Interpretation
At Pg 6-7 of the response, Applicants assert that the interpretation of “isolated” is inaccurate.
Words in claims are given their ‘plain meaning’ unless such meaning is inconsistent with the specification (See MPEP 2111.01(I)). The “plain meaning” of ‘isolated’ is considered “occurring alone or once” (See Merriam-Webster online dictionary, 2025). When used in the context of cell populations, “isolated” means ‘separation of one cell population from a heterogeneous mixture of cells’ (See StemCell Technologies “Cell Separation Techniques: Everything you need to know about cell isolation”, Pg 1).
It is appreciated that the presumption that a term is given its ordinary and customary meaning can be rebutted by the applicant by clearly setting forth a different definition of the term in the specification (See MPEP 2111.01(I)). However, in the instant case the definition does not clearly provide an alternative definition. The definition provided in the specification states that “an isolated ABCB5(+) stem cell” refers to a cell that has been removed from an organism in which it was originally found, or a descendent of such a cell.” (emphasis added) This definition does not clearly broaden the ordinary and customary meaning to no longer require isolation/separation from other cells. A cell which is isolated/separated is necessarily removed from the originating organism. The line “The term “isolated” does not preclude the later use of the cell thereafter in combinations or mixtures with other cells or in an in vivo environment” (emphasis added) is understood to mean that an initially isolated cell can later be mixed with other cells. However, upon mixing with other cells, the cell is now part of a heterogenous mixture, which is different than an ‘isolated’ cell population.
Therefore, “isolated ABCB5(+) limbal stem cells” will still be interpreted as meaning the cells are free of non-ABCB5(+) limbal stem cells (i.e. the ABCB5(+) limbal stem cells are separated from non ABCB5(+) limbal stem cells). It is further pointed out that the stated interpretation has been consistently applied throughout the prosecution of the two parent applications. The interpretation made of record was critical for allowability of claims in the parent cases over the prior art, specifically over Ma et al (Stem Cells, 2006) (see, e.g. Notice of allowance dated 6/21/2017 in 14/768885).
RE: Rejection of claims 62-65 and 67-73 under 35 USC 112, second paragraph: Cancellation of claims 67 and 68 render the rejection of these claims moot.
The amendment to claims 62-65 obviate the previous basis of rejection, but a new rejection has been necessitated.
Applicants have traversed the rejection of claims 69-73 asserting that the term “isolated ABCB5(+) limbal stem cells” does not exclude non-ABCB5(+) limbal stem cells. For the reasons set forth above in Response to Claim Interpretation, this is not found persuasive. The rejection is maintained.
RE: Rejection of claims 1, 8-10, 12 and 69-73 under 35 USC 112, first paragraph, as failing to comply with the enablement requirement:
Applicants have traversed the rejection of record asserting that the specification provides sufficient guidance on isolation and identification of ABCB5+ limbal stem cells, and evidence of their use in promoting ocular regeneration sufficient to enable the full scope of the claims.
This argument is not found persuasive because the evidence in the specification only supports that ABCB5+ LSCs can successfully regenerate damaged corneal epithelium. Specifically, Example 4 shows that ABCB5+ LSCs provide treatment in animals with LSCD. There is no clear disclosure or support in the original specification for use of ABCB5+ LSCs for treating any other ocular conditions. The rejection is modified to address the current limitations.
RE: Rejection of claims 57-61 under 35 USC 101:
Initially it is noted that claim 59 should not have been included in the rejection heading. Claim 59 was not under rejection (as an isolated human cornea does not contain retinal cells, much less ABCB5(+) retinal stem cells).
Cancellation of claims 58 and 60 render the rejections thereof moot.
The amendment to claim 57 to require the in vitro substrate to be seeded with a population of cells enriched with isolated ABCB5(+) stem limbal stem cells does differentiate from natural cornea. Natural cornea contains a native level of ABCB5(+) cells, not an enriched level. The rejection is withdrawn from claims 57, 59 and 61.
RE: Rejection of claims 40-42 under 35 USC 102(b) over Frank et al: The amendment to claim 40 to require the ABCB5+ stem cells to comprise ABCB5+ ocular stem cells is effective to differentiate from the ABCB5+ dermal MSC-seeded matrices of Frank. The rejection is withdrawn.
RE: Rejection of claims 40-43, 57, 58, 60 and 66-68 under 35 USC 102(b) over Ma et al:
Cancellation of claims 41-43, 58, 60, 67 and 68 render the rejections thereof moot.
The amendment to claim 66 to depend from claim 59 overcomes the rejection thereof.
Applicants have traversed the rejection of record asserting that claim 40 now requires the isolated ABCB5+ stem cells are a population of ABCB5+ ocular stem cells enriched for limbal stem cells, and that Ma et al does not teach ABCB5+ ocular stem cells enriched for limbal stem cells.
This argument is not found persuasive because the claim is unclear what is required (See Rejection under 35 USC 112, second paragraph, above). Ma et al teach a denuded amniotic membrane seeded with limbal stem cells. The amniotic membrane is thus enriched with limbal stem cells (as denuded amniotic membrane naturally contains no limbal stem cells). Furthermore, Ksander et al evidence that LSCs contain a subpopulation of ABCB5(+) limbal stem cells (See Ksander, abstract). Therefore, it is submitted that the LSCs of Ma et al inherently contained at least some ABCB5(+) limbal stem cells. Therefore the graft of Ma et al is an ocular graft enriched with limbal stem cells, including ABCB5+ limbal stem cells. The rejection is maintained over amended claims 40 and 57.
RE: Rejection of claims 57, 58, 60, 61, 66-68 under 35 USC 102(b) over Woodward et al:
Cancellation of claims 58, 60, 67 and 68 render the rejections thereof moot.
The amendment to claim 66 to depend from claim 59 overcomes the rejection thereof.
The amendment to claim 57 to require the in vitro substrate to be seeded with a population of cells enriched with isolated ABCB5(+) stem limbal stem cells does differentiate from natural cornea. Natural cornea contains a native level of ABCB5(+) cells, not an enriched level. The rejection is withdrawn from claims 57, 59 and 61.
RE: Rejection of claims 1, 8-10, 12, 31, 32, 39-43, 57, 58, 60 and 62-75 over claims of US Patent 9801912:
Applicants state a terminal disclaimer has been filed over US Patent 9801912, but no such terminal disclaimer has been filed.
The rejection is maintained over the claims remaining pending.
RE: Rejection of claims 40-42 on grounds of NSDP over US Patent 10017738:
The amendments to the claims to require ABCB5+ ocular stem cells is effective to differentiate over the patented claims. The rejection is withdrawn.
RE: Rejection of claims 1, 8-10, 31, 32, 39-43, 57, 60, and 62-75 on grounds of NSDP over US Patent 11446331:
The amendments to the claims to require presence ABCB5+ limbal stem cells is effective to differentiate over the patented claims. The rejection is withdrawn.
Claim Interpretation
The application is generally directed to use of ABCB5+ limbal stem cells. The following points are made of record to assist in understanding the scope of the claims:
Not all ABCB5+ cells are limbal stem cells. ABCB5 is a marker found on a number of cell types, including limbal stem cells, retinal pigment stem cells, stem cells found in central cornea, mesenchymal stem cells from a variety of sources, including skin, and some cancer stem cells (See instant specification, Ksander et al (Nature, 2014), Frank US Patent 8455245, Thill et al (Melanoma Research, 2011)).
ABCB5+ ocular stem cells will include, inter alia, ABCB5+ limbal stem cells, ABCB5+ retinal pigment stem cells, ABCB5+ stem cells from central cornea region, and ABCB5+ mesenchymal stem cells derived from the eye.
Not all ocular stem cells, nor all limbal stem cells, are ABCB5+. This is supported by the fact that ABCB5 knock out mice (i.e. all cells lack expression of ABCB5) still have some limbal stem cells and central corneal cells (See Ksander et al, id). Thus, ABCB5+ ocular stem cells is a subpopulation of ocular stem cells, and ABCB5+ limbal stem cells is a subpopulation of limbal stem cells
“Isolation” of a particular cell type will be interpreted to mean that no cells not meeting the requirement are present. E.g. ‘An isolated population of ABCB5+ limbal stem cells’ means no ABCB5- limbal stem cells are present, nor any non-limbal stem cells, are present.
“Enrichment” of a particular cell type will be interpreted to mean that the concentration of said cell type in a population has been increased relative to its native concentration. Enrichment can be achieved by removing non-target cells or by adding in additional target cells. E.g. ‘An enriched population of ABCB5(+) limbal stem cells’ means that the number of ABCB5+ limbal stem cells in the population is greater than the native concentration in the population.
In light of the above points, the claims are interpreted as follows:
Claim 1 is directed to a method of treating a subject having an ocular condition comprising administering isolated ABCB5+ limbal stem cells in an amount effective to regenerate ocular cells in the subject. Noting that the claim requires administration of ‘isolated’ ABCB5+ limbal stem cells, it is interpreted that no other cells will be administered along with the ABCB5+ ocular stem cells. The ocular condition is limited to those conditions that ‘benefit from regeneration of ocular cells’.
Claim 8 requires the cells be administered as an ocular graft, and for the ocular graft to comprise an artificial cornea comprised of the ABCB5+ ocular stem cells. The specification defines “ocular graft for transplantation” as a substrate containing ACBC5+ stem cells and optionally other ocular cells and bioactive factors that promote ocular cell regeneration, which substrate may be transplanted to or implanted into an eye of a subject to replace damaged or infected tissue (See Pg. 20 of as-filed spec). There is no definition for ‘artificial cornea’ in the instant application. Thus, in giving the claim its broadest reasonable interpretation, any substantially planar material that is transplantable to or implantable into an eye will be considered to satisfy definition of ‘an artificial cornea’. (Noting that the cornea is substantially planar). Regarding the limitation that the artificial cornea ‘be comprised of’ ABCB5+ ocular stem cells, this is interpreted as meaning the artificial cornea comprises ABCB5+ ocular stem cells.
Claims 9 and 10 the adjectives “allogeneic” and “syngeneic” are understood to describe the relationship between the isolated ABCB5+ limbal stem cells and the subject being treated.
Claim 31 is directed to a method of producing an ocular graft for transplantation into a subject. The method comprises a single active step of seeding a substrate with isolated ocular ABCB5+ limbal stem cells to produce the ocular graft. The specification defines “ocular graft for transplantation” as a substrate containing ACBC5+ stem cells and optionally other ocular cells and bioactive factors that promote ocular cell regeneration, which substrate may be transplanted to or implanted into an eye of a subject to replace damaged or infected tissue (See Pg. 20 of as-filed spec). In light of the definition in the specification, the preamble ‘breathes life into the claim’ in so far as it requires that the method result in production of a graft that is suitable for transplantation to or implantation into an eye of a subject. However, actual transplantation and/or implantation is not required by claim 31. Noting that the claim requires seeding of the substrate with isolated ABCB5+ limbal stem cells, it is interpreted that no other cells will be seeded along with the ABCB5+ limbal stem cells.
Claim 32 requires further administration of the substrate (i.e. the ocular graft) into a subject. Claim 32 further defines the limbal stem cells as allogeneic stem cells. This is understood to mean the stem cells are allogeneic to the recipient of the ocular graft.
Claims 74 and 75 describe the manner in which the ABCB5+ ocular stem cells are obtained. These are product-by-process limitations. Product-by-process limitations are considered only in so far as the method of production affects the final product. In this case, the manner in which ABCB5+ limbal stem cells are isolated does not change the biochemistry or phenotype of the ABCB5+ limbal stem cells.
Claim 40 is directed to an ocular graft enriched with isolated ABCB5(+) ocular stem cells enriched for limbal stem cells. As above, the specification defines “ocular graft for transplantation” as a substrate containing ACBC5+ stem cells and optionally other ocular cells and bioactive factors that promote ocular cell regeneration, which substrate may be transplanted to or implanted into an eye of a subject to replace damaged or infected tissue (See Pg. 20 of as-filed spec). There are no specific structural or construction details beyond ‘capable of being transplanted to or implanted into an eye.” Claim 40 now limits the ABCB5(+) cells to ocular stem cells, and further requires the ocular stem cells to be enriched for limbal stem cells. The product is described as being enriched with isolated cells, this is interpreted as meaning the final graft must have a concentration of ABCB5(+) ocular stem cells greater than the native number of ABCB5(+) stem cells on the graft. Adding even a single ABCB5(+) ocular stem cell to a graft will achieve this effect. The graft does not exclude additional ABCB5(-) cells. However, the claim goes on to describe the ABCB5(+) ocular stem cells as being enriched for limbal stem cells. Given that not all limbal stem cells are ABCB5(+), this new limitation raises a rejection under 35 USC 112, second paragraph, as it is not clear what is ultimately being required.
Claim 57 is drawn to an in vitro substrate, comprising an artificial cornea substrate seeded with a population of cells enriched with isolated ABCB5+ limbal stem cells. There is no definition for ‘artificial cornea’ in the instant application. Thus, in giving the term its broadest reasonable interpretation, any substantially planar material that is transplantable to or implantable into an eye will be considered to satisfy definition of ‘an artificial cornea’. The claim requires the artificial cornea to be seeded with a population of cells enriched with isolated ABCB5+ limbal stem cells. This is interpreted as meaning the final graft must have a concentration of ABCB5(+) limbal stem cells greater than the native number of ABCB5(+) limbal stem cells on the graft. If the substrate is a non-corneal tissue, then even a single ocular ABCB5(+) limbal stem cell will satisfy this limitation. Other cells (including ABCB5- limbal stem cells and ABCB5+ non-limbal cells) can also be present. Overall, the claim is interpreted as being drawn to an in vitro substrate comprising (i) a substantially planar material that is transplantable to or implantable into an eye, and (ii) ABCB5+ limbal stem cells.
Claim 61 is interpreted as requiring the cell population to further comprise cells from the central cornea. It is noted that limbal stem cells are from the limbus, not from the central cornea.
Claim 59 is drawn to an in vitro substrate, comprising an artificial cornea substrate seeded with a population of cells enriched with isolated ABCB5+ retinal stem cells. There is no definition for ‘artificial cornea’ in the instant application. Thus, in giving the term its broadest reasonable interpretation, any substantially planar material that is transplantable to or implantable into an eye will be considered to satisfy definition of ‘an artificial cornea’. The claim requires the artificial cornea to be seeded with a population of cells enriched with isolated ABCB5+ retinal stem cells. This is interpreted as meaning the final graft must have a concentration of ABCB5(+) retinal stem cells greater than the native number of ABCB5(+) retinal stem cells on the graft. If the substrate is a non-retinal tissue, then even a single ocular ABCB5(+) retinal stem cell will satisfy this limitation. Other cells (including ABCB5- retinal stem cells and ABCB5+ non-retinal cells) can also be present. Overall, the claim is interpreted as being drawn to an in vitro substrate comprising (i) a substantially planar material that is transplantable to or implantable into an eye, and (ii) ABCB5+ retinal stem cells.
New/Maintained Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 8-10, 12, 62-65 and 69-73 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1, 8-10, 12, and 69-73: Claim 1 has been amended to limit the ‘ocular conditions’ being treated to conditions which benefit from regeneration of ocular cells. The metes and bounds of ocular conditions which benefit from regeneration of ocular cells is not clear. Broadly, ocular conditions encompasses any disease, disorder or condition which affects the eye. The eye is a complex organ which includes several different tissue structures, including, inter alia, the cornea, conjunctiva, iris, pupil, anterior chamber, posterior chamber, vitreous body, retina, macula, and optic nerve. Any disease, disorder or conditions which affects any of these tissue structures falls within the scope of ‘ocular conditions’. Thus ocular conditions includes physical damage to any one or more of the eye structures; inflammation or infection of any one or more of the eye structures; diseases/conditions specific to individual eye structures (i.e. optic neuritis affects the optic nerve, macular degeneration affects the macula, retinitis pigmentosa affects the retina, cataracts affects the lens, glaucoma is increased intraocular pressure (i.e. affecting the vitreous body), but ultimately affects the optic nerve); conditions wherein symptoms affect the eye (i.e. Sjogren's syndrome, Stevens-Johnson syndrome); cancers present in any one or more of the eye structures; and more. Each of aforementioned types of ocular conditions each have different causes and affect different physiological processes. Various treatment modalities were available for different types of conditions, but as treatments continue to develop, it is unknown which of these conditions could benefit from regeneration of ocular cells. There is no clear indication in the specification nor prior art of which diseases or conditions could benefit from regeneration of any one or more types of ocular cells. It is understood that conditions characterized by physical damage to any one or more eye structures would benefit from regeneration of ocular cells, but it cannot readily be determined which other types of conditions might benefit from regeneration of one or more types of ocular cells.
Claims 2-8, 12 and 69-73 depend from claim 1, inherit the deficiency, and thus are rejected on the same basis.
Regarding claim 8: there is now insufficient antecedent basis for the limitation “the ABCB5+ ocular stem cells”.
Regarding claim 40: Limbal stem cells are a type of ocular stem cell. But not all ocular or limbal stem cells are ABCB5+. Thus it is unclear what is meant by requiring that the ABCB5+ ocular stem cells are enriched for limbal stem cells. Are they enriched for ABCB5+ limbal stem cells? If not, then it appears that the claim includes a broadening limitation.
Regarding claims 62-65: It is unclear if the claims are attempting to require at least X% of the cells in the cell population to be ABCB5(+) retinal stem cells, or if the claims are attempting to require that at least X% of the cells can be any ABCB5(+) stem cell. As multiple interpretations of the claim are possible, the metes and bounds are unclear.
Regarding claims 69-73: Claim 1 requires administration of isolated ABCB5+ limbal stem cells. Words in claims are given their ‘plain meaning’ unless such meaning is inconsistent with the specification (See MPEP 2111.01(I)). The “plain meaning” of ‘isolated’ is considered “occurring alone or once” (See Merriam-Webster online dictionary, 2025). When used in the context of cell populations, “isolated” means ‘separation of one cell population from a heterogeneous mixture of cells’ (See StemCell Technologies “Cell Separation Techniques: Everything you need to know about cell isolation”, Pg 1). Therefore, “isolated ABCB5(+) limbal stem cells” is interpreted as meaning the cells are free of non-ABCB5(+) limbal stem cells (i.e. the ABCB5(+) limbal stem cells are separated from non ABCB5(+) limbal stem cells). As such, the ABCB5+ limbal stem cells must make up 100% of the cell population. Claims 69-73, which permit for the ABCB5+ limbal stem cells to be as low as 1.0% of the total cell population thus do not correlate in scope. The metes and bounds of the claims are unclear.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 8-10, 12 and 69-73 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 has been amended to define the ocular condition being treated as one which benefits from regeneration of ocular cells. The limitation appears to have been added to address that administration of specific cell subtypes does not reasonably provide enablement for treatment of any ocular condition. The limitation that the ocular conditions are now limited to a subset of ocular conditions that would benefit from regeneration of ocular cells is thus a narrowed subset of the broader (previously claimed) genus of ocular conditions. The specification discloses examples of ocular conditions that would benefit from regeneration of ocular cells, namely limbal stem cell deficiency (¶0006), macular degeneration (See ¶0007), and ocular wounds (¶0008), but these species are not clearly representative of the full scope of ocular conditions which would benefit from regeneration of ocular cells. There is determined to be insufficient disclosure to show Applicants have support for the narrowed scope of ocular conditions that would benefit from regeneration of ocular cells. Claims 2-8, 12 and 69-73 depend from claim 1, inherit the deficiency, and thus are rejected on the same basis.
This is a new matter rejection. The new matter must be removed in response to this office action.
Claims 1, 8-10, 12 and 69-73 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating ocular conditions caused by damage to corneal epithelium, including ocular conditions due to limbal stem cell deficiency (LSCD), including blindness due to LSCD, and/or methods for regenerating corneal epithelial cells, by administering ABCB5(+) limbal stem cells (LSCs), does not reasonably provide enablement for the full scope of the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Regarding the breadth of the claims:
Claims 1, 8-10 and 69-73 are broadly directed to treatment of any ocular condition which can benefit from regeneration of ocular cells, by administering isolated ABCB5(+) limbal stem cells.
Broadly, ocular conditions encompasses any disease, disorder or condition which affects the eye. The eye is a complex organ which includes several different tissue structures, including, inter alia, the cornea, conjunctiva, iris, pupil, anterior chamber, posterior chamber, vitreous body, retina, macula, and optic nerve. Any disease, disorder or conditions which affects any of these tissue structures falls within the scope of ‘ocular conditions’. Thus ocular conditions includes physical damage to any one or more of the eye structures; inflammation or infection of any one or more of the eye structures; diseases/conditions specific to individual eye structures (i.e. optic neuritis affects the optic nerve, macular degeneration affects the macula, retinitis pigmentosa affects the retina, cataracts affects the lens, glaucoma is increased intraocular pressure (i.e. affecting the vitreous body), but ultimately affects the optic nerve); conditions wherein symptoms affect the eye (i.e. Sjogren's syndrome, Stevens-Johnson syndrome); and cancers present in any one or more of the eye structures. The causes of the aforementioned ocular conditions each have different causes, affect different physiological processes, and are treated with different agents. There is no clear indication of which diseases or conditions could benefit from regeneration of any one or more types of ocular cells. It is understood that conditions characterized by physical damage to any one or more eye structures would benefit from regeneration of ocular cells, but it cannot readily be determined which other types of conditions might benefit from regeneration of one or more types of ocular cells.
Therefore, claims 1, 8-10 and 69-73 encompass treatment of physical damage to any of the eye structures by administration of isolated ABCB5(+) limbal stem cells, as well as potentially treating additional ocular conditions that are not characterized by damaged or lost ocular cells, by administration of isolated ABCB5(+) limbal stem cells.
Regarding the nature of the invention: Broadly, the nature of all claims is stem cell-based therapy for ocular diseases. More specifically, the nature of the invention of claims 1, 8-10, 12 and 69-73 is treatment of any of the above described ocular conditions via administration of limbal stem cell isolated based on ABCB5 expression.
Regarding the state of the prior art: With regards to the state of the art regarding stem cell-based therapies for ocular conditions: Eveleth provides a review of the state of the art of cell-based therapies for ocular conditions as of 2013 (the time the instant application was filed) (Eveleth, J Ocular Pharmacol Ther, 2013). For treatment of corneal epithelial cells Eveleth describe transplantation of intact cornea was known, and the field of transplantation of LSCs was promising, but still nascent. LSCs are capable of giving rise to limbal epithelial cells of the cornea. LSC transplantation is most effective for treatment in patients with burns, but is less successful in patients with corneal epithelial defects due to Stevens-Johnson Syndrome or congenital connective tissue disorders (See Eveleth, Pg. 845, 1st column, 1st full paragraph). For treatment of corneal endothelial cells transplantation of corneal endothelial cells is the standard of care. Eveleth reports there is no recognized stem or progenitor cells which are capable of giving rise to corneal endothelial cells, thus treatment by transplantation with stem or progenitor cells is not recognized as effective (See Eveleth, Pg. 845, 2nd column "Corneal endothelial cells"). For treatment of corneal stromal defects, Eveleth do not report effective cell-based therapies, but states that research is underway to identify stromal stem cells (See Eveleth, Pg. 845, 2nd column “Corneal stroma”). For retinal disorders, Eveleth report that several cell-based therapies are in clinical trials, including techniques wherein embryonic stem cells are induced to retinal pigment epithelial cells (RPE cells), or RPE cells, per se, or other retinal, or neural cells are transplanted (See Eveleth, Pgs 846-850). For treatment of glaucoma, transplantation of retinal ganglion cells is suggested, but has numerous hurdles prior to implementation in humans (See Eveleth, Pg. 850 "Glaucoma"). Eveleth conclude that LSC transplantation for treatment of chemical burns and diseases of the corneal epithelial surface is the most accepted/used, yet as of 2013 cell-based therapies for treatment of corneal endothelium, corneal stroma, and retinal diseases are still under development (See Eveleth, Pg. 851 "Summary and Conclusion”).
Other prior art work supports the conclusion of Eveleth, showing that LCS are capable of regenerating damaged corneal epithelial cells, and that such restoration is effective to restore vision due to LSCD (See Ma et al, Stem Cells, 2006; Rama et al, NEJM, 2010). In addition to LSC, MSCs are also taught as being capable of regenerating damaged corneal epithelial cells, and that such restoration is effective to restore vision to due to LSCD (See Ma et al, id; and Frank et al (US 2008/0003206).
Thus the prior art supports that only a limited number of ocular conditions, namely those limited to corneal epithelial defects caused by physical damage, were potentially treatable by administration of LSCs. There was no teaching or suggestion in the prior art that limbal stem cells could regenerate ocular cells beyond corneal epithelial cells.
With regards to ABCB5+ ocular stem cells: at the time the invention was made ABCB5 was generally referenced as a marker of cancer stem cells (See Wilson et al, Cancer Res, 2011; Thill et al, Melanoma Res, 2011; Setia et al, Mod Pathol, 2012). Frank et al (US 2008/0003206) is the first and only prior-art disclosure of ABCB5 being a marker of non-cancer cells, specifically Frank et al disclose ABCB5(+) dermal MSCs as being effective to treat inflammatory and autoimmune conditions. Frank et al have a suggestion that ABCB5(+) dermal MSCs can also be used to treat corneal disease (See Frank et al ¶0066).
The prior art does not identify ABCB5 as a marker of LSCs or any other type of ocular stem cell.
Regarding the level of ordinary skill in the art: An ordinary artisan in the area of stem cell-based therapies would have experience in selecting cells needing replacement/regeneration in vivo, isolating and culturing stem cells to determine their capability to differentiate into the desired cell type in vivo, and carrying out animal testing wherein the selected cells are administered to animal models of disease and the results are monitored. While determining what type of cell is to be replaced in vitro, determination of what stem or progenitor cells can successfully differentiate into said desired cell type in vivo is generally not well-known or routine, given the complexity of cell differentiation mechanisms, changes in environments between in vitro and in vivo conditions and other various factors that affect cell differentiation. Because in vivo conditions do not have the controlled conditions that can be made in vitro, even models which are predicative of a particular differentiation pathway in vitro do not necessarily undergo the same differentiation pathway in vivo. Furthermore, in all stem and progenitor cell transplantations the possibility for unchecked growth and tumor formation is always a possibility.
Regarding the level of predictability in the art: The art recognized repair of corneal epithelial defects by administration of MSCs (including ABCB5+ MSCs) and LSCs as well known (See Ma et al, Rama et al, Frank et al). However, the art teaches stem cell-based therapies for other corneal diseases (i.e. diseases which affect the corneal stromal and/or the corneal endothelium) as still unpredictable, and method of stem-cell based therapies for retinal disorders as still in clinical trial stages (See Eveleth). There was a high level of unpredictability in the field of stem-cell based therapies, in general, as the differentiation potential of any particular stem cell is highly unpredictable. ABCB5 stem cells were generally only known as cancer stem cells, and thus were unsuitable for therapeutic use. Therefore, the predictability of using any ABCB5+ ocular stem cell (as permitted by claims 1,8-10 and 69-73) for treatment of any ocular condition (claims 1, 8-10, 12 and 69-73) was low at the time the invention was made.
Regarding the amount of guidance and working examples: The instant specification identifies LSCs as ABCB5+ and discloses how to isolate ABCB5+ LSCs (Example 1). The instant specification exemplifies transplantation of ABCB5+ limbal epithelial cells (i.e. ABCB5+ LSCs) to subjects with induced LSCD and report the transplanted cells generated new corneal epithelial cells (Example 4). This evidence supports that ABCB5+ LSCs can successfully regenerate damaged corneal epithelium. The specification does not provide any additional guidance or examples involving treatment of any ocular condition besides corneal epithelial defects (including LSCD) using ABCB5+ LSC, nor effect of LSC on ocular tissues outside of the corneal epithelium. Thus, the specification provides sufficient teachings only for enablement of treatment of damaged corneal epithelium/regeneration of corneal epithelial cells by transplantation of ABCB5+ LSCs. The art teaches that blindness due to LSCD is due to destruction of the corneal epithelium (Rama et al). Therefore the teachings of the specification can further be extrapolated to support treatment of blindness due to LSCD by transplantation of ABCB5+ LSCs.
In conclusion, the evidence provided in the instant specification, in light of the teachings available in the art, only support treatment of damaged corneal epithelium/regeneration of corneal epithelial cells and treatment of blindness due to LSCD by transplantation of ABCB5+ LSCs. In the field of stem cell-based therapies, the predictability was too great to expect ABCB5(+) LSCs to treat ocular conditions outside of this scope. Determination of other ocular conditions which may be treated and/or methodology necessary to successfully treat any other ocular conditions using ABCB5+ limbal stem cell would require undue experimentation.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claims 40 and 57 are rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Ma et al (Stem Cells, 2006), evidenced by Ksander et al (Nature, 2014).
Ma et al compare efficacy of corneal grafts comprising amniotic membranes seeded with one of human fibroblasts, MSCs, or limbal stem cells (LSCs)(See Ma et al, Pg. 318 “Results” and Fig. 1C-1F).
Ksander et al is relied upon to evidence that LSCs contain a subpopulation of ABCB5(+) limbal stem cells (See Ksander, abstract). Therefore, it is submitted that the LSCs of Ma et al inherently contained at least some ABCB5(+) limbal stem cells.
Regarding claims 40: The ocular graft comprising human LSCs on amniotic membrane reads on an ocular graft enriched with isolated ABCB5(+) limbal stem cells for transplantation into a subject. The graft clearly reads on an ocular graft, as it is intended for application to the cornea. Limbal stem cells are ocular stem cells. For reasons noted above, the human LSC population used by Ma et al will inherently contain an ABCB5(+) subpopulation. Addition of even one ABCB5(+) limbal stem cell to the amniotic membrane is effective to enrich the ocular graft for ABCB5(+) limbal stem cells.
Regarding claim 57: The ocular graft comprising human LSCs on amniotic membrane reads on an in vitro substrate comprising an artificial corneal substrate seeded with a cell population enriched with isolated ABCB5(+) limbal stem cells. The cell-seeded amniotic membrane has a substantially planar shape, thus it satisfies the physical property of an artificial cornea. For reasons noted above, the human LSC population used by Ma et al will inherently contain an ABCB5(+) subpopulation. Addition of even one ABCB5(+) limbal stem cell to the amniotic membrane is effective to enrich the ocular graft for ABCB5(+) limbal stem cells.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 8-10, 12, 31, 32, 39, 40, 57, 60 and 69-73 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 9801912.
Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims anticipate and/or render obvious the instant claims.
Regarding claims 1 and 12: Patented claim 1 anticipates claims 1 and 12.
Regarding claim 8: Patented claim 4 teaches administering ABCB5+ LSCs as an ocular graft. Though the patented claim does not teach the form of the ocular graft, selection of a substrate that is substantially planar so as to permit application to the cornea would have been prima facie obvious, as the method is intended to regenerate corneal cells. Such an ocular graft will read on an artificial cornea comprising ABCB5+ LSCs.
Regarding claim 9: Patented claim 5 teaches the limitation of current claim 9.
Regarding claim 10: Patented claim 6 teaches the limitation of current claim 10.
Regarding claims 69-73: The patented claims require administration of an isolated population of ABCB5+ LSCs. Thus the ABCB5+ LSCs are 100% of the cell population being administered.
Regarding claim 31: Patented claim 4 states the isolated ABCB5+ LSCs are administered as an ocular graft. Thus, an ocular graft comprising the ABCB5+ LSCs must first be produced in order to be administered. Patented claim 4 is thus considered to at the least render obvious production of an ocular graft comprising ABCB5+ LSCs. Seeding the cells on the graft substrate is prima facie obvious.
Regarding claim 32: The designation of allogeneic does not distinguish the cells in any way.
Regarding claim 39: Selection of any well-known substrate material appropriate for application to the eye, including those listed, would have been prima facie obvious.
Regarding claims 74-75: For reasons discussed under Claim Interpretation, claims 74-75 are product-by-process limitations and do not further limit the ABCB5+ limbal stem cells.
Regarding claim 40: Patented claim 4 states the isolated ABCB5+ LSCs are administered as an ocular graft. Thus, an ocular graft comprising the ABCB5+ LSCs is considered disclosed by the patented claim.
Regarding claim 57: Patented claim 4 states the isolated ABCB5+ LSCs are administered as an ocular graft. Thus, an ocular graft comprising the ABCB5+ LSCs is considered disclosed by the patented claim. Though the patented claim does not teach the form of the ocular graft, selection of a substrate that is substantially planar so as to permit application to the cornea would have been prima facie obvious, as the method is intended to regenerate corneal cells. Such an ocular graft will read on an artificial cornea comprising ABCB5+ LSCs.
Claim Objections
Claim 61 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Allowable Subject Matter
Claims 59 and 66 are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M FOX whose telephone number is (571)272-2936. The examiner can normally be reached M-F 10-6 EST.
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/ALLISON M FOX/Primary Examiner, Art Unit 1633