DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed 3/25/26 in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/3/26 has been entered.
Claims 1 and 4-13 are pending and are under examination.
In view of Applicant’s claim amendments, the previous rejections under 35 U.S.C. 102 and 103 are withdrawn.
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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, 4-13 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Specifically, there is insufficient written description to demonstrate that applicant was in possession of the claimed genus of EGFL7 peptide comprising a polypeptide sequence “at least 90% identical to the full length sequence of SEQ ID NO: 1”.
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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the claimed genus. See MPEP 2163.
The present claims are directed to a method of treating GVHD in a subject, comprising administering a recombinant EGFL7 peptide comprising a polypeptide sequence at least 80% identical to the full length of SEQ ID NO: 1. The claims encompass EGFL7 peptide variants that can differ by as much as 10% to the EGFL7 of SEQ ID NO: 1. The claims encompass a large genus of structurally different peptides with distinct amino acid sequences with up to 27 amino acids differing from the SEQ ID NO: 1. The claims require that the peptides function in treating GVHD and dependent claims specify additional functions such as inducing T cell exhaustion or decreasing the level of inflammatory cytokine and/or adhesion molecules in the subject. The state of the art is such that protein chemistry is one of the most unpredictable areas of biotechnology. Whisstock et al (Quarterly Review of Biophysics, 2003, 36, pp307-340) teach that the prediction of protein function from sequence and structure is a difficult problem, because homologous proteins often have different functions. Even single amino acid changes in a proteins amino acid sequence can have dramatic effects on protein function. For example, Wang et al., 2001, show that a single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipids growth factor receptors (e.g., abstract). These references demonstrate that even a single amino acid substitution or what appears to be an inconsequential chemical modification will often dramatically affect the biological activity and characteristic of a peptide. Furthermore, EGFL7 is a complex protein with numerous functional domains including emilin like domain, which interacts with extracellular matrix proteins, EGF-I domains that can bind Notch receptor, EGF-II domains that bind calcium ions, an RGD domain that binds integrins, as well as a coiled coil, for which the role in EGFL7 structure or function is unclear (see Fabian, 2025). The fact that EGFL7 does not interact with a single and specific molecule makes the design of modulators able to mimic all biological function of EGFL7 a challenge (See Uphaus, 2018). Thus, EGFL7 peptide variants are not well known in the art, nor is there an art recognized correlation between structure and function. The instant specification discloses using a full length EGFL7 protein of SEQ ID NO: 1, but does not disclose any specific species of variants of EGFL7 of SEQ ID NO: 1 that differ by up to 10% of the full length sequence. Thus, the specification does not disclose a representative number of species, nor does the specification disclose a correlation between structure and function for the genus of claimed peptides that function to treat GVHD.
The instant application has not provided a sufficient description showing possession of the necessary 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 applicant was in possession of the genus of peptides. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
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.)
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Applicant’s arguments filed 3/3/26 have been fully considered, but they are not persuasive.
Applicant argues that the specification on page 11 discloses a EGFL7 peptide having at least 90% identity and therefore the present claims are fully supported by the specification.
The present claims, as amended encompass a very large genus of peptide, having up to 10% difference or 27 amino acids as compared to SEQ ID NO: 1. The only disclosed species of EGL7 peptide is SEQ ID NO: 1, which is not sufficiently representative of the genus of peptides encompassed by the instant claims. Nor does the specification provide a correlation between peptide structure and the claimed functions. One of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Claims 1 and 4-13 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 GVHD in a subject comprising administering to the subject a therapeutically effective amount of a recombinant EGFL7 peptide, wherein the recombinant EGFL7 peptide comprises the polypeptide sequence of SEQ ID NO: 1;
does not reasonably provide enablement for:
A method of treating GVHD in a subject comprising administering to the subject a therapeutically effective amount of a recombinant EGFL7 peptide, wherein the peptide comprises a polypeptide sequence 90% identical to SEQ ID NO: 1.
The specification disclosure is insufficient to enable one skilled in the art to practice the invention as claimed without an undue amount of experimentation. Undue experimentation must be considered in light of factors including: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill in the art, the level of predictability of the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention, in re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988).
“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 in 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 to how to make and use the invention in order to be enabling (MPEP 2164.03)” The MPEP further states that physiological activity can be considered inherently unpredictable.
The present claims are directed to a method of treating GVHD in a subject, comprising administering a recombinant EGFL7 peptide comprising a polypeptide sequence at least 90% identical to the full length sequence of SEQ ID NO: 1. The claims encompass EGFL7 peptide variants that can differ by as much as 10% to the EGFL7 of SEQ ID NO: 1. The claims encompass a large genus of structurally different peptides with distinct amino acid sequences with up to 27 amino acids differing from the SEQ ID NO: 1. The claims require that the peptides function in treating GVHD and dependent claims specify additional functions such as decreasing the level of inflammatory cytokine and/or adhesion molecules in the subject. The state of the art is such that protein chemistry is one of the most unpredictable areas of biotechnology. Whisstock et al (Quarterly Review of Biophysics, 2003, 36, pp307-340) teach that the prediction of protein function from sequence and structure is a difficult problem, because homologous proteins often have different functions. Even single amino acid changes in a proteins amino acid sequence can have dramatic effects on protein function. For example, Wang et al. , 2001, show that a single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipids growth factor receptors (e.g., abstract). These references demonstrate that even a single amino acid substitution or what appears to be an inconsequential chemical modification will often dramatically affect the biological activity and characteristic of a peptide. Furthermore, EGFL7 is a complex protein with numerous functional domains including emilin like domain, which interacts with extracellular matrix proteins, EGF-I domains that can bind Notch receptor, EGF-II domains that bind calcium ions, an RGD domain that binds integrins, as well as a coiled coil, for which the role in EGFL7 structure or function is unclear (see Fabian, 2025). The fact that EGFL7 does not interact with a single and specific molecule makes the design of modulators able to mimic all biological function of EGFL7 a challenge (See Uphaus, 2018). Thus, making and using any EGFL7 peptides at least 90% identical to SEQ ID NO: 1 for treating GVHD, inducing T cell exhaustion, decreasing inflammatory cytokines and adhesion molecules would be highly unpredictable.
Thus, based on the breadth of the claims and the unpredictability of the art, the instant specification must provide a sufficient and enabling disclosure, commensurate in scope with the instant claims. The instant specification discloses an example wherein a full length EGF7 polypeptide diminishes GVHD severity in an mouse model. However, no guidance or examples are provided regarding peptides 90% identical to SEQ ID NO:1. Thus, based on the breadth of the claims, the unpredictability of the art, and the lack of guidance provided by the instant specification, it would require undue experimentation to practice the method as broadly claimed.
Applicant’s arguments filed 3/3/26 have been fully considered, but they are not persuasive.
Applicant argues that a sequence at least 90% identical would allow for point mutations or deletions, and one skilled in the art would have a reasonable expectation of success.
The state of the art is such that protein chemistry is one of the most unpredictable areas of biotechnology. Whisstock et al (Quarterly Review of Biophysics, 2003, 36, pp307-340) teach that the prediction of protein function from sequence and structure is a difficult problem, because homologous proteins often have different functions. Even single amino acid changes in a proteins amino acid sequence can have dramatic effects on protein function. For example, Wang et al. , 2001, show that a single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipids growth factor receptors (e.g., abstract). Applicant cites no evidence to the contrary, nor does Applicant point to any teachings of the specification that provide guidance or examples regarding which changes could be tolerated. Furthermore, EGFL7 is a complex protein with numerous functional domains including emilin like domain, which interacts with extracellular matrix proteins, EGF-I domains that can bind Notch receptor, EGF-II domains that bind calcium ions, an RGD domain that binds integrins, as well as a coiled coil, for which the role in EGFL7 structure or function is unclear (see Fabian, 2025). The fact that EGFL7 does not interact with a single and specific molecule makes the design of modulators able to mimic all biological function of EGFL7 a challenge (See Uphaus, 2018). Thus, making and using any EGFL7 peptides or fragments thereof or polypeptides at least 90% identical to SEQ ID NO: 1 for treating GVHD, inducing T cell exhaustion, decreasing inflammatory cytokines and adhesion molecules would be highly unpredictable. Thus, based on the breadth of the claims, the unpredictability of the art, and the lack of guidance provided by the instant specification, it would require undue experimentation to practice the method as broadly claimed.
The following are new grounds of rejection.
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.
Claim(s) 1, 4, 6-13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2019/049939 (of record).
WO2019/049939 teaches a method of inducing stem cell proliferation in a subject by administering to the subject EGFL7, wherein the stem cells are allogeneic stem cells that have been transplanted into the subject (i.e. administration after allogeneic stem cell transplant, see page 16, in particular). WO2019/049939 teaches administering wildtype EGFL7 protein encoded by SEQ ID NO: 2, which encodes a protein 100% identical to SEQ ID NO: 1 of the instant application. The instant specification discloses that GVHD is a condition that results from transplantation of donor stem cells and that treatment with EGFL7 can be prophylactic (See pages 11 and 16, in particular). Therefore, the subjects that have been transplanted with allogeneic (i.e. donor) stem cells in WO2019/049939 are inherently “in need of treatment” for GVHD, and are within the scope of the instant claims. WO2019/049939 teaches administration of therapeutically effective amounts of EGFL7 protein in a by an intravenous route, and administration as a series of doses, and as a pharmaceutical formulation (see paragraphs 107-109, in particular). WO2019/049939 teaches that the stem cells are bone marrow cells and teaches treating bone marrow transplant subjects (See paragraph 97, in particular). The method would inherently treat GVHD and mitigate symptoms thereof, induce T cell exhaustion and decrease adhesion and cytokines, since this is an inherent property of EGFL7 administration.
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.
Claim 1, 4-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2019/049939 (of record).
The teachings of WO2019/049939 are described above. Although WO2019/049939 does not explicitly teach daily administration after said transplantation, optimizing the timeframe of the series of doses, including daily administration after stem cell or bone marrow transplant to maintain levels of EGFL7 for therapeutic efficacy would be routine and well within the purview of the ordinary artisan. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
Claims 1 and 4-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2013/061112, in view of Sackstein, 2006.
WO2013/061112 teaches administering EGFL7 to inhibit transendothelial migration of immune cell in a subject who has received a graft or transplant, wherein the method prevents rejection (see page 7-8, in particular). WO2013/061112 also teaches administration of EGFL7 in a subject with an inflammatory disease, wherein the Egfl7 inhibits T lymphocyte infiltration (see pages 8-9, in particular). WO2013/061112 explains that EGFL7 prevents the normal activation of vascular endothelium and prevents transmigration of leukocytes through endothelium into tissues during inflammatory processes (see page 1-2, in particular). WO2013/061112 teaches EGFL7 of SEQ ID NO; 2, which is 100% identical to SEQ ID NO: 1 of the instant application (see page 3, in particular). WO2013/061112 teaches intravenous administration and in a pharmaceutically acceptable carrier (see page 10, in particular).
The reference differs from the claimed invention in that it does not explicitly teach that the transplant subject is in need of treatment for GVHD .
Sackstein teaches that GVHD is a T cell mediated inflammatory disease that occurs after bone marrow transplantation, and that it involves migration of effector T cells from the graft into target tissues such as the skin, gut, and liver. Sackstein teaches that GVHD can be treated by preventing effector immune cells from migrating to target tissues.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made that administration of EGFL7 to the transplant patient in WO2013/061112, could be performed in a transplant patient in need of treatment for GVHD to suppress GVHD based on the teachings of Sackstein. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because WO2013/061112 teaches that EGFL7 administration inhibits T lymphocyte infiltration and suppresses inflammatory disease, and Sackstein teaches that GVHD is a T lymphocyte mediate inflammatory disease that can be treated by preventing T lymphocyte migration to target tissues. Thus, the ordinary artisan would expect to suppress skin and livery injury by preventing infiltration of inflammatory T cells by EGFL7 administration. Furthermore, optimizing the timeframe of administration, such as daily dosing after transplantation to suppress inflammation would be routine and well within the purview of the ordinary artisan. Regarding the limitations of inducing T cell exhaustion or decreasing inflammatory cytokine or adhesion molecule expression, this is a latent property which would flow naturally from EGFL7 administration.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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