Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Applicant’s amendments and remarks filed on September 17, 2025 are acknowledged. Claims 2, 6, 11-14, 16, 19, 25, 26, and 28 have been canceled. Claims 1, 4, and 8 were amended. Claims 1, 3-5, 7-10, 15, 17, 18, 20-24, 27, and 29-31 are pending. Claims 7, 15, 23, 24, and 27 are withdrawn.
Claims 1, 3-5, 8-10, 17, 18, 20-22, and 29-31 are examined on the merits herein.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(a) written description and 35 U.S.C 102 rejections are withdrawn.
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 3 and 5 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.
Claims 3 and 5 are incomplete because the claims recite “The method of claim 2” and claim 2 is canceled. See MPEP 2173.05(e); 608.01(n), part (V). In the interest of compact prosecution, the Examiner is interpreting claims 3 and 5 as being dependent on claim 1.
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.
Enablement
Claims 1, 3-5, 8-10, 17, 18, 20-22, and 29-31 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 a method of treating a disease or condition of the eye in a subject wherein the disease or condition of the eye is characterized by choroidal neovascularization comprising administering a toll-like receptor 7 (TLR7) agonist to an eye of the subject, wherein the TLR7 agonist is selected from the group consisting of imiquimod, resiquimod, loxoribine, gardiquimod, vesatolimod, GS-986, and combinations of two or more thereof, does not reasonably provide enablement for a method of treating any other disease or condition of the eye in a subject wherein the disease or condition of the eye is characterized by ocular nerve degeneration or damage comprising administering a toll-like receptor 7 (TLR7) agonist to an eye of the subject, or for administering any other TLR7 agonist to treat choroidal neovascularization. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is
sufficient evidence to support a determination that a disclosure does not satisfy the
enablement requirement and whether any necessary experimentation is “undue”.
These factors include, but are not limited to: (A) The breadth of the claims; (B) The
nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary
skill; (E) The level of predictability in the art; (F) The amount of direction provided by the
inventor; (G) The existence of working examples; and (H) The quantity of
experimentation needed to make or use the invention based on the content of the
disclosure.
Breadth of claims and nature of the invention:
Claims 1, 3-5, 8-10, 17, 18, 20-22, and 29-31 are drawn to a method of treating a disease or condition of the eye in a subject, wherein the disease or condition of the eye is characterized by corneal or retinal neovascularization or ocular nerve degeneration or damage, the method comprising administering a toll-like receptor 7 (TLR7) agonist to an eye of the subject.
State of the prior art, level of predictability in the art, and level of one of
ordinary skill:
Simmons et al. (Investigative Ophthalmology & Visual Science 2016) discloses that toll-like receptors are expressed by epithelial and immune cells in the eye and are involved in response to infection and induction of inflammation on the ocular surface [page 2443, left column, first paragraph]. Simmons et al. also discloses that there are limited treatment options available for dry eye. While toll-like receptors are known to promote inflammation, their role in dry eye has not been fully explored [page 2447, right column, third full paragraph].
Xiao et al. (Journal of Immunology 2016) discloses that dysfunction of Tregs was reported in active uveitis patients. A significant decrease in Tregs was observed in a CL097-treated patient group compared with the control group, implying an inhibiting effect of TLR7 activation on Treg generation which is in agreement with recent reports showing that TLR7 activation negatively regulates Tregs. Further, the reduction in the percentages of Tregs may account, in part, for the more severe disease in CL097-treated mice [page 3829, left column, first full paragraph]. This is evidence of the unpredictability associated with treating diseases or conditions by the steps of the claimed methods, particularly autoimmune and/or inflammatory diseases or conditions.
Liu et al. (Survey of Ophthalmology 2018) discloses that the unique anatomical position and relative immune privilege of cornea make it an ideal tissue for gene-based therapies. However, current treatment options for corneal neovascularization are restricted by limited efficacy, adverse effects, and a short duration of action [abstract]. While gene therapy seems to be effective in animal studies, safety issues arising from the vectors and transgenic overexpression may limit clinical utility. In addition, the mode of delivery requires further refinement. Liu et al. further discloses that the success of gene therapy seen in some animal studies is accomplished by early and frequent administration, which is far from ideal for treating ongoing corneal neovascularization [page 205, left column, section 8]. Although Liu et al. discloses that success has been achieved in animal models, Campochiaro et al. (Human Gene Therapy 2017) showed that despite long term expression (2.5 to 4 years), endostatin expression was not therapeutic in age-related macular degeneration [abstract].
Maharjan et al. (Journal of Pharmaceutical Investigation 2019) discloses that drug delivery to targeted ocular tissues has posed significant and considerable challenges due to the nature of ocular diseases and the presence of numerous ocular barriers [page 225, first full paragraph].
Campos et al. (Nanomedicine: Nanotechnology, Biology, and Medicine 2017) discloses that the treatment of eye diseases affecting the posterior segment is quite challenging due to the anatomy, physiology, and biochemistry of the eye [abstract]. Campos et al. also discloses that being able to assure and maintain therapeutic doses of drugs in the target tissues remain a significant challenge [page 2101, left column bridging to right column].
Kobold et al. (Immunotherapy 2014) discloses that in addition to the natural ligand single-stranded RNA, other classes of TLR7 agonists have been described and can be grouped into the imidazoquinolones (or ‘imiquimod-like’ ligands) and guanosine analogs with varying specificity for TLR7. Studies that directly compare the biological activity of different TLR7 agonists in relevant models or in patients are lacking. However, synthetic compounds such as imiquimod or 852A may be superior for in vivo application compared with RNA owing to TLR7 selectivity and in vivo stability [page 1086, left column, third full paragraph]. Chi et al. (Frontiers in Pharmacology 2017) discloses that the development of many TLR agonists has been discontinued in consequence of lacking efficacy in phase III trial [page 1, first paragraph].
Amount of direction provided by the inventor and existence of working
examples:
The instant specification as filed envisions that the methods and compositions can be used to treat diseases or conditions characterized by e.g., neovascularization of one or more tissues of the eye including e.g., the cornea, the retina, or the choroid. In addition, the specification envisions methods and compositions to treat diseases or conditions characterized by ocular (e.g., corneal) nerve degeneration or damage [page 7, second paragraph]. The specification further provides a list of diseases or conditions that are characterized by neovascularization, retinal neovascularization, and choroidal neovascularization [page 7, last two paragraphs and page 8, first paragraph].
In example 1, the specification discloses that pDCs promote nerve regeneration and neurite outgrowth in vitro and in vivo in part through secretion of nerve growth factor (NGF). In addition, stimulating pDCs through TLR7 can enhance secretion of NGF and consequently promote neurite outgrowth via phosphorylating cAMP response element-binding protein by p38 mitogen-activated protein (MAP) kinase. The evidence in the specification suggests that pDCs promote vascularization of the cornea so it would not be used to treat corneal neovascularization and thus is contrary to what is claimed.
In example 2, the specification teaches that treatment of splenic cells from wildtype mice with either Imiquimod (TLR7 agonist) or CpG-ODN (TLR9 agonist) increases the percentage of endostatin-secreting pDCs as well as the median fluorescent intensity of endostatin staining, showing expression of higher levels of endostatin by pDCs following treatment with TLR7 or TLR9 agonists. However, the specification does not provide guidance for an artisan to practice the method of treating a disease or condition of the eye in a subject comprising administering a toll-like receptor 7 (TLR7) agonist to an eye of the subject including ones characterized by neovascularization or ocular nerve degeneration or damage as claimed.
While the instant specification discloses on page 8, lines 34-37 that the agonists can be administered in amounts determined to be appropriate by those of skill in the art and provides examples of exemplary amounts of TLR7 agonists for administration, the specification does not provide adequate guidance as to what a therapeutic dose of any TLR7 agonist is. Further, the specification does not address or provide guidance as to how the dose can be predictably delivered to the appropriate eye compartment to overcome the state of the art.
Quantity of experimentation:
The quantity of experimentation necessary to carry out the full scope of the claimed invention is large, as the skilled artisan could not rely on the prior art or the present specification to teach how to make and use the full scope of the claimed methods. With any one agonist and one disease or condition of the eye characterized by neovascularization or ocular nerve degeneration or damage one would have to determine how to deliver the agonist to the appropriate target cells with specificity and efficiency, and how to induce at least some therapeutic effect. Since neither the prior art nor the specification provides the answers to all of these questions, it would require a large quantity of trial and error experimentation by the skilled artisan to do so.
In view of the state and level of predictability in the art and the failure to provide adequate guidance to overcome the state and level of predictability of the art, one of skill would have to perform undue experimentation in order to practice the invention commensurate in scope with the claims.
Response to Arguments
Applicant's arguments filed September 17, 2025 have been fully considered but they are not persuasive.
Applicant amended claim 1 to recite “A method of treating a disease or condition of the eye in a subject, wherein the disease or condition of the eye is characterized by corneal or retinal neovascularization or ocular nerve degeneration or damage”. As indicated in the 35 U.S.C. 112(a) enablement rejection, the specification is enabled for a method of treating a disease or condition of the eye in a subject wherein the disease or condition of the eye is characterized by choroidal neovascularization comprising administering a toll-like receptor 7 (TLR7) agonist to an eye of the subject, wherein the TLR7 agonist is selected from the group consisting of imiquimod, resiquimod, loxoribine, gardiquimod, vesatolimod, GS-986, and combinations of two or more thereof (emphasis added).
Applicant asserts that the data described on pages 17-18 of the application show by in vivo studies in mice that administration of TLR7 agonists to the eye stimulates plasmacytoid dendritic cells to have increased nerve growth factor mRNA levels. Applicant further asserts that TLR7 agonist presence in co-cultures of trigeminal ganglion cells with pDCs enhances neurite outgrowth which demonstrates that TLR7 agonist use results in increased NGF production and thus results in nerve growth. Applicant also asserts that the in vivo results show that administration can result in a meaningful effect (e.g., increased NGF mRNA levels) which counters any concerns of whether administered agents can be effective in vivo. However, the specification does not provide guidance for an artisan to practice the method of treating a disease or condition of the eye in a subject comprising administering a toll-like receptor 7 (TLR7) agonist to an eye of the subject including ones characterized by ocular nerve degeneration or damage.
With respect to Applicant’s arguments against the Simmons et al., Liu et al., Maharjan et al., and Kobold et al. references, these references were cited to establish the state of the prior art at the time of the claimed invention. To reiterate, Simmons et al. taught that while toll-like receptors are known to promote inflammation, their role in dry eye has not been fully explored. Liu et al. taught that current treatment options for corneal neovascularization are restricted by limited efficacy, adverse effects, and a short duration of action. As evidenced by Maharjan et al., drug delivery to targeted ocular tissues has posed significant and considerable challenges due to the nature of ocular diseases and the presence of numerous ocular barriers. Further, Kobold et al. taught that studies that directly compare the biological activity of different TLR7 agonists in relevant models or in patients are lacking.
Thus, one of skill would have to perform undue experimentation in order to practice the invention commensurate in scope with the claims. Therefore, the Examiner is maintaining the 35 U.S.C. 112(a) enablement rejection.
Conclusion
No claims are allowed.
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.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637