DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant’s correspondence filed June 6, 2024, is acknowledged. Claims 1-8 are pending and presently subject to examination.
Objection to the Specification
3. The instant specification is objected to for the following reasons:
There are trademarks in this application that do not meet the requirements.
The use of the term (e.g., “Algerbrush” at para. [0038] and “Hamilton” at para. [0042]), which is a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology whenever possible; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please, review the specification for other improper trademarks and correct as required.
Claim Rejections - 35 USC § 112
4. 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.
Written Description
5. Claims 1-8 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 claims contain 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that:
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
No Written Description for the Breadth of the Claims: methods for treating lattice corneal dystrophy (LCD) with TGFBI therapeutics. Applicant is not in possession of any methods of treating LCD or LCD therapeutics.
Claim 1 recites a method for treating lattice corneal dystrophy (LCD) comprising administering recombinant transforming growth factor beta induced (TGFBI) protein or a TGFBI protein-expressing reagent. Claims 2-5 further recite formulation types of the recombinant TGFBI protein-containing reagent; that the recombinant TGFBI expressing reagent is e.g., a vector; and modifying the recombinant TGFBI protein / expressing reagent. Claims 6-8 are directed to drugs for treating LCD comprising the recombinant TGFBI protein or a TGFBI protein-expressing reagent.
The claims therefore broadly encompass methods of treating LCD, and TGFBI therapeutics for treating LCD. Note: although claims 6-8 are directed to a product, they recite the intended use of being “for treating LCD,” and thus also require written description support for this intended use.
The specification discloses corneal erosion assays at FIGs. 2-3 and 5, wherein TGFBI R124C point mutation-carrying mice are subjected to corneal scraping with a brush. The rate of corneal healing is assayed in R124C controls and compared to R124C mice receiving various forms of the TGFBI drugs. Improved rates of corneal healing are shown for the R124C mice receiving the TGFBI drugs compared to controls. The specification does not disclose how old the R124C mice were when the experiments were performed; whether the mice used were homozygous or heterozygous for the R124C mutation; or if any hallmarks of LCD were present in the mouse corneas prior to the experiments, such as TGFBI amyloid deposits.
The claims require that LCD be treated with the TGFBI therapeutics. The specification indicates at para. [0034] that the mouse model used (TGFBI R124C) “could” develop LCD symptoms such as corneal opacity, however no corneal opacities—let alone amyloid deposits—associated with LCD are demonstrated in the specification. For example, although the specification does not describe the state of the mouse corneas prior to the experiments, at least FIGs. 2 and 3 show that the corneas of the R124C control mice had no opacities 72 hours after the wound healing experiments. In other words, the experiments disclosed by the specification indicate that the mice used in the experiments did not have hallmark / required features of LCD, despite the mice having the TGFBI R124C point mutation. Therefore, the breadth of the claims—requiring treatment of LCD—is not commensurate with the specification’s disclosure. To address this issue, a brief assessment of the state of the art of LCD and the murine model (R124C) employed by Applicant are made herein, which shows that the hallmark feature of LCD is corneal opacity caused by the accumulation of TGFBI amyloid bodies; and that the R124C murine model does not develop said amyloid bodies until advanced age, if at all. Therefore, the specification’s disclosure of corneal erosion assays—in TGFBI R124 mice of unknown age and having unknown TGFBI R124C zygosity— does not read on treatments for LCD as instantly claimed because: treatment of LCD requires removal the TGFBI amyloid bodies associated with LCD, since said amyloid bodies are the hallmark feature of LCD and the feature that disturbs vision in LCD.
Lattice corneal dystrophy type I (https://www.medlineplus.gov/download/genetics/condition/lattice-corneal-dystrophy-type-i.pdf: 2012) (“LCD1”) is a brief review of LCD etiology. LCD1 teaches at the first paragraph that: “Lattice corneal dystrophy type I is an eye disorder that affects the clear, outer covering of the eye called the cornea. The cornea must remain clear for an individual to see properly; however, in lattice corneal dystrophy type I, protein clumps known as amyloid deposits cloud the cornea, which leads to vision impairment.” LCD1 further teaches the secondary effect of recurrent corneal erosions; that LCD is caused by protein deposits in the cornea; and that LCD is caused by TGFBI mutations that cause it to clump and form the amyloid deposits.
Kitamoto et al. ("Generation of mouse model of TGFBI-R124C corneal dystrophy using CRISPR/Cas9-mediated homology-directed repair." Scientific reports 10.1 (2020)) is the research article describing the murine TGFBI R124C model used by Applicant. Kitamoto et al. show at FIG. 2 that corneal “opacity” does not fully develop until R124C mice are about 24 weeks of age. At 24 weeks of age, about 80% of R124C homozygous mice have bilateral corneal opacities, and only about 10% of R124C heterozygous mice have bilateral corneal opacities. Kitamoto et al. concludes at page 7, last paragraph: “The TGFBI-R124C mutant mice might not be reliable as a model of LCD1, given that amyloid deposition was not detected in these mice[,]” but “delayed wound healing in mutant mice was similar to that observed in human patients with R124C LCD.” Kitamoto et al. postulate about the reasons for the lack of amyloid deposits at the first paragraph of pg. 7: “our mice likely required more time to form amyloid plaques. Furthermore, because the lifespan of mice is shorter than that of humans, it is possible that there was not sufficient time to form amyloid plaques in our mice.” Kitamoto et al. therefore show that although the R124C mice can develop “opacities” and show delayed wound healing similar to that observed in LCD, TGFBI R124C mice do not develop the hallmark TGFBI amyloid deposits. It is furthermore apparent from the instant specification that the R124C mice used by Applicant did not have LCD because: the corneas of the R124C control mice did not have opacities, let alone amyloid deposits.
Therefore, without performing the required experiment of treating LCD, it is unpredictable how the instantly claimed TGFBI therapeutics may effectuate a treatment for LCD. Neither the art nor the specification provides a sufficient representative number of examples where administering TGFBI clears the TGFBI amyloid deposits associated with LCD to meet the written description for instant claims directed to the treatment of LCD with the TGFBI therapeutics. This is at least because: it is unclear how administering WT TGFBI protein will alleviate the TGFBI clumping that forms the amyloid deposits that are a hallmark of LCD. The TGFBI R124C model used by applicant does not reproduce this hallmark feature of LCD, as noted by Kitamoto et al. Applicant has instead demonstrated treatment of a secondary feature of LCD: corneal erosion associated with LCD. It is therefore highly unlikely that that the instantly claimed therapeutics can treat LCD. Accordingly, Applicant has not demonstrated possession of any of the instantly claimed subject matter.
No Written Description for the Breadth of the Claims: “modifying the recombinant TGFBI protein” (i.e., claim 3) or modifying the mRNA (i.e., claim 5). Applicant is not in possession of any recombinant TGFBI protein modifications.
Claim 3 recites: further comprising modifying the recombinant TGFBI protein; and claim 5 recites a modified mRNA. The specification describes these modifications as being related to sustained action of the TGFBI protein / mRNA at e.g., para. [0026].
The claims therefore broadly encompass the inclusion of modifications to the TGFBI protein structure (or mRNA encoding the TGFBI protein) that confers sustained action of the therapeutic—for example, half-life improvement.
The specification does not disclose any modified TGFBI proteins or mRNAs. The specification solely discloses administration of the commercially available—and unmodified (other than His tag)— TGFBI from SinoBiological having catalog no: 10569-H08H (see instant para. [0023]) or AAV carrying WT TGFBI.
The claims recite functional language of the modified TGFBI protein / mRNA, such as treating LCD; however, a definition by function does not suffice to define the genus of modified TGFBI proteins / mRNAs because it is only an indication of what the modified TGFBI protein / mRNA does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of modified TGFBI proteins / mRNAs is highly variable (i.e., each modified TGFBI protein / mRNA would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed modified TGFBI proteins / mRNAs have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art regarding the unpredictability of protein modifications, e.g., Fc fusions to extend protein therapeutic half-life, is made herein, which shows that substantial experimentation is required to achieve beneficial modifications of the protein therapeutics.
Binder et al. ("Strategies for extending the half-life of biotherapeutics: successes and complications." Expert Opinion on Biological Therapy 25.1 (2025): 93-118) is a review about therapeutic protein modifications and teaches that many therapeutic proteins have short half-lives when administered directly; and that e.g., Fc fusion can extend half-life. See Binder et al. at Table 1. Regarding Fc fusion technology, Binder et al. teach that Fc and linker selection/optimization is critical to preserving the activity of the protein: “[a] critical component of Fc fusion proteins is the linker, which can significantly affect the binding activity of the fusion partner, as shown for dulaglutide (Trulicity®) [… .] Whereas fusion of the GLP-1 derivative via the natural hinge region to an IgG1 Fc reduced potency in vitro by 95% in comparison to the free peptide, optimization of linker length and sequence, together with the choice of an Fc from the IgG4 subclass, led to a four-fold improvement.” Binder et al. at page 104, right col. In other words, a person of skill in the art would readily appreciate that significant unpredictability exists around how to construct e.g., Fc fusion proteins to modify the TGFBI proteins / mRNAs. Binder et al. show that various techniques to extend half-life have been applied to different proteins, e.g., PEGylation, FC fusion, hyper glycosylation, albumin fusion, and lipidation. See Binder et al. at Table 1. However, substantial experimentation is required to obtain a solution that extends the half-life while retaining the functionality of the protein. For example, regarding possible PEGylation solutions, Binder et al. teach: “examples underline that there is no universal plug-and-play solution for PEGylation of biopharmaceuticals. Rather, the coupling chemistry, choice of linker, type of PEG macromolecule – branched, linear, short or long chain – and the conjugation site(s) within the pharmacologically active protein or peptide must be optimized individually[.]” Binder et al. at page 98, left col. Binder et al. therefore shows that it is very unpredictable what members of the genus modified TGFBI protein / mRNA may work to treat LCD; and Applicant has not demonstrated, or even suggested, any examples of said modifications in the specification.
Therefore, without performing any of the required experiments, it is unpredictable how TGFBI may be “modified” to effectuate treatment of LCD. Neither the art nor the specification provides a sufficient representative number of examples of modified TGFBI proteins or mRNAs to meet the written description of instant claims directed such subject matter. This is at least because: the art indicates it is unpredictable how to modify a therapeutic protein to retain or improve the therapeutic effect; and Applicant has not presented any examples of modified TGFBI proteins / mRNAs to demonstrate possession of the genus of modifications. Applicant has not demonstrated possession of treatment of LCD with TGFBI protein / mRNA—let alone with modified TGFBI proteins / mRNAs, if it is even possible. It is therefore wholly unknown which modified TGFBI proteins or mRNAs will treat LCD. Applicant therefore has not demonstrated possession of any of the instantly claimed subject matter.
Given all of the above, Applicant does not have possession for methods of treating LCD with recombinant TGFBI proteins or protein-expressing agents, let alone treatment of LCD with modified TGFBI proteins or mRNAs. Applicant is not in possession of any of the instantly claimed subject matter.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
6. Claim 3 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The specification does not reasonably provide enablement for methods of treating sepsis by administering inhibitors of the biomarkers.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(2) The breadth of the claim:
Claim 3 is drawn to: modifying the recombinant TGFBI protein. The specification describes these modifications as being related to sustained action of the TGFBI protein at e.g., para. [0026].
The claims therefore broadly encompass the inclusion of modifications to the TGFBI protein structure that confers sustained action of the therapeutic—for example, half-life improvement.
(5) The predictability or unpredictability of the art:
The state of the art indicates that it is very unpredictable how to modify recombinant TGFBI protein to achieve sustained TGFBI action.
It is unpredictable how to “modify” recombinant TGFBI protein; Applicant has not shown how to make and use any recombinant TGFBI proteins having modifications.
The claim requires LCD to be treated with the modified recombinant TGFBI protein; however, the specification does not disclose any modified TGFBI proteins, let alone treatment of LCD with a modified recombinant TGFBI protein. To address this issue, a brief assessment of the state of the art regarding the unpredictability of protein modifications, e.g., Fc fusions to extend protein therapeutic half-life, is made herein, which shows that substantial experimentation is required to achieve beneficial modifications of the protein therapeutics because it not predictable which modifications will achieve the desired result.
Binder et al. ("Strategies for extending the half-life of biotherapeutics: successes and complications." Expert Opinion on Biological Therapy 25.1 (2025): 93-118) is a review about therapeutic protein modifications and teaches that many therapeutic proteins have short half-lives when administered directly; and that e.g., Fc fusion can extend half-life. See Binder et al. at Table 1. Regarding Fc fusion technology, Binder et al. teach that Fc and linker selection/optimization is critical to preserving the activity of the protein: “[a] critical component of Fc fusion proteins is the linker, which can significantly affect the binding activity of the fusion partner, as shown for dulaglutide (Trulicity®) [… .] Whereas fusion of the GLP-1 derivative via the natural hinge region to an IgG1 Fc reduced potency in vitro by 95% in comparison to the free peptide, optimization of linker length and sequence, together with the choice of an Fc from the IgG4 subclass, led to a four-fold improvement.” Binder et al. at page 104, right col. In other words, a person of skill in the art would readily appreciate that significant unpredictability exists around how to construct e.g., Fc fusion proteins to modify the recombinant TGFBI proteins. Binder et al. show that various techniques to extend half-life have been applied to different proteins, e.g., PEGylation, FC fusion, hyper glycosylation, albumin fusion, and lipidation. See Binder et al. at Table 1. However, substantial experimentation is required to obtain a solution that extends the half-life while retaining the functionality of the protein. For example, regarding possible PEGylation solutions, Binder et al. teach: “examples underline that there is no universal plug-and-play solution for PEGylation of biopharmaceuticals. Rather, the coupling chemistry, choice of linker, type of PEG macromolecule – branched, linear, short or long chain – and the conjugation site(s) within the pharmacologically active protein or peptide must be optimized individually[.]” Binder et al. at page 98, left col. Binder et al. therefore shows that it is very unpredictable what members of the genus modified recombinant TGFBI protein may work to treat LCD; and Applicant has not demonstrated, or even suggested, any examples of said modifications in the specification.
Given all the above, the cited reference demonstrates that it is very unpredictable which of the encompassed recombinant TGFBI protein modifications will result in sustained action of the recombinant TGFBI protein and treatment of LCD. Applicant has not performed the required experiments to teach one of ordinary skill in the art how to make and use a single species of modified recombinant TGFBI—that treats LCD—encompassed by the claims.
(6) the amount of direction or guidance provided by the inventor:
As noted above, the specification provides no examples of modified recombinant TGFBI proteins, let alone said proteins that treat LCD. Given all the above, one of skill in the art could not reasonably extrapolate the instant findings regarding unmodified recombinant TGFBI protein to modified versions thereof. It would be undue experimentation to determine which modifications would result in sustained action of the recombinant TGFBI protein and/or effectuate a treatment for LCD.
(8) the quantity of experimentation needed to make or use the invention:
It would be undue experimentation to make or use the invention encompassed by the breadth of claim 3 because each recombinant TGFBI protein modifications encompassed by the claim would need to be tested to determine which may effectuate a treatment for LCD. In contrast, Applicant has not demonstrated how to make and use even a single embodiment of the claimed invention. As the above-cited references demonstrate, it is therefore highly unpredictable which of the encompassed modified recombinant TGFBI proteins may treat LCD.
In conclusion, the claimed invention does not provide enablement for modifications to recombinant TGFBI protein, let alone treatment of LCD with said modified proteins. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claim, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claim and the specification is not fully enabled for the instant claim. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claim Rejections – 35 USC § 112(b)
7. 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 6-8 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.
A. Claim 6 recites the phrase “and a pharmaceutically acceptable auxiliary material.” The term “pharmaceutically acceptable” is a relative term which renders the claim indefinite. The term “pharmaceutically acceptable” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree of “acceptable,” and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the claim-recited “pharmaceutically acceptable auxiliary materials” are indefinite. Appropriate clarification and/or correction is required.
B. Claim 8 recites that that the dosage form of the externally applied drug “is a microneedle.” It is unclear how a dosage form can be a microneedle, which is a device for delivering the drug. The claim would be clearer if it recited e.g., that the dosage form “is formulated for a microneedle.” Appropriate clarification and/or correction is required.
Claim 7 is rejected for depending from an indefinite claim.
Claim Rejections – 35 USC § 102
8. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
9. Claims 1 and 4-8 are rejected under 35 U.S.C 102 (a)(2) as anticipated by Laulicht et al. (WO2022036256A1; published February 17, 2022). The earliest date to which the instant application claims priority is March 19, 2024.
Claim 1 encompasses, in the alternative, a method for treating a subject with lattice corneal dystrophy (LCD), wherein a recombinant TGFBI protein-expressing reagent is administrated to the subject in need thereof.
Claim 4 encompasses a method of claim 1, wherein the recombinant TGFBI protein-expressing reagent is a vector for expressing a recombinant TGFBI protein.
Claim 5 encompasses a method of claim 4, further comprising modifying the vector, for expressing the recombinant TGFBI protein.
Claim 6 encompasses a drug for treating LCD, comprising a recombinant TGFBI protein-expressing reagent that serves as an active ingredient and a pharmaceutically acceptable auxiliary material.
Claim 7 encompasses a drug of claim 6, wherein a dosage form of the drug is an injection drug.
Claim 8 encompasses a drug of claim 7, wherein the dosage form of the externally applied drug is a microneedle.
Laulicht et al. discloses a method for treating a subject with lattice corneal dystrophy (LCD) by administering a recombinant TGFBI protein-expressing reagent.
Laulicht et al. is directed to systems and methods for injection of therapeutics into ocular tissue (see, e.g., para. [0002]). Laulicht et al. disclose the injection system may be used to deliver a gene therapy that targets, replaces, inhibits, or promotes e.g., TGFBI to impart therapeutic effect at para. [0129]. Laulitch et al. disclose the disease being treated may be e.g., lattice corneal dystrophy (LCD) at para. [0144]. Laulitch et al. disclose use of AAV vectors having serotypes 1-11—and variants thereof—with the invention at para. [0125]; Laulitch et al. therefore necessarily discloses administering a recombinant TGFBI protein-expressing reagent, and modifications thereof, to treat a patient having LCD (claims 1 and 4-5).
Laulicht et al. further discusses pharmaceutically acceptable auxiliary material, e.g., hydrogels for increasing residence time of the injected therapeutic at para. [0134] (claims 6-7).
Laulicht et al. further discusses their invention as an improvement over microneedle administration at para. [0004] (claim 8).
Accordingly, Laulicht et al. anticipates claims 1 and 4-8.
Claim Rejections - 35 USC § 103
10. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
11. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
12. Claims 1-2 and 4-8 are rejected under 35 U.S.C 103 as obvious over Laulicht et al. (WO2022036256A1; published February 17, 2022) in view of Hardet et al. ("Oral-tolerization prevents immune responses and improves transgene persistence following gene transfer mediated by adeno-associated viral vector." Molecular Therapy 24.1 (2016): 87-95).
Claim 1 encompasses a method for treating a subject with lattice corneal dystrophy (LCD), wherein a recombinant transforming growth factor beta induced (TGFBI) protein, a recombinant TGFBI protein-containing reagent or a recombinant TGFBI protein-expressing reagent is administrated to the subject in need thereof.
Claim 2 encompasses a method according to claim 1, wherein the recombinant TGFBI protein-containing reagent comprises an aqueous solution of the recombinant TGFBI protein.
Claim 4 encompasses a method of claim 1, wherein the recombinant TGFBI protein-expressing reagent is a vector for expressing a recombinant TGFBI protein.
Claim 5 encompasses a method of claim 4, further comprising modifying the vector, for expressing the recombinant TGFBI protein.
Claim 6 encompasses a drug for treating LCD, comprising a recombinant TGFBI protein or a recombinant TGFBI protein-expressing reagent that serves as an active ingredient and a pharmaceutically acceptable auxiliary material.
Claim 7 encompasses a drug of claim 6, wherein a dosage form of the drug is an injection drug.
Claim 8 encompasses a drug of claim 7, wherein the dosage form of the externally applied drug is a microneedle.
Laulicht et al. is directed to systems and methods for injection of therapeutics into ocular tissue (see, e.g., para. [0002]). Laulicht et al. disclose the injection system may be used to deliver a gene therapy that targets, replaces, inhibits, or promotes e.g., TGFBI to impart therapeutic effect at para. [0129]. Laulitch et al. disclose the disease being treated may be e.g., lattice corneal dystrophy (LCD) at para. [0144]. Laulitch et al. disclose use of AAV vectors having serotypes 1-11—and variants thereof—with the invention at para. [0125]; Laulitch et al. therefore necessarily discloses administering a recombinant TGFBI protein-expressing reagent, and modifications thereof, to treat a patient having LCD. Laulicht et al. also discusses concerns with AAV administration, specifically the immune response to AAV gene therapy, and suggests administration of other agents that suppress immune response to enable multiple injections of gene therapy at para. [0145]. Laulicht et al. discusses pharmaceutically acceptable auxiliary material, e.g., hydrogels for increasing residence time of the injected therapeutic at para. [0134]. Laulicht et al. further discusses their invention as an improvement over microneedle administration at para. [0004].
Laulicht et al. do not explicitly disclose administering a TGFBI protein-containing agent in aqueous solution.
Hardet et al. discloses a method to reduce immune response to AAV therapeutics (see the title). Hardet et al. discuss in the abstract that AAV therapy is hampered by immune responses directed against the vector and against the transgenic protein; and that prophylactic oral administration of the immunogenic protein before AAV-mediated gene transfer completely prevented antibody formation and cytotoxic CD8+ T-cell response. The last sentence of the abstract concludes: Hence, gene therapy may represent an ideal situation where oral-tolerization can be adopted before or at the same time as vector injection to efficiently prevent deleterious immune responses directed against the transgenic protein. Hardet et al. also discloses that the protein (Ova) was dissolved in water for adminstration (i.e., an aqueous solution) at pg. 93 (materials and methods—Oral Ova protein administration).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to modify the recombinant TGFBI gene therapy for LCD as taught by Laulicht et al. to additionally or first administer the recombinant TGFBI protein because: Laulicht et al. teaches the risks of gene therapy, namely the immune response to gene therapy, and broadly suggests that other agents may be considered for administration to reduce the immune response risk. Hardet et al. addresses the same immune response problem by administering the therapeutic protein in aqueous solution prior to administering AAV gene therapy of the same protein. One of ordinary skill in the art would therefore be motivated to administer recombinant TGFBI in aqueous solution with a reasonable expectation of success because: Hardet et al. broadly teaches that the administration of therapeutic proteins will reduce immune response to subsequent gene therapy to the same protein. Therefore, one of ordinary skill in the art would conclude with a reasonable expectation of success that the teachings of Laulicht et al. and Hardet et al. would render instant claims 1-2 and 4-8 obvious.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." The combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine the prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Accordingly, Laulicht et al., in view of Hardet et al., renders claims 1-2 and 4-8 obvious.
Pertinent Art
13. The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure:
Chitnis et al. (WO2021055906A1; published March 25, 2021) discloses similar subject matter to Laulicht et al., cited in the 35 U.S.C. 102 and 103 rejections made of record herein.
Conclusion
14. No claim is allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached on M-Th from 7 to 4 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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