DETAILED ACTION
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 .
Claim Status
Applicant’s preliminary amendments received 22DEC2023 are acknowledged.
Claims 14-16 have been canceled.
Claims 1-2, 4-9, 11-13, and 17-22 have been amended.
Claims 1-13 and 17-22 are pending in the instant application (i.e., Claim(s) 1-2 is/are independent).
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/US2022/035114, filed 27JUN2022, which claims the benefit of US Provisional Patent Application No. 63/215499, filed 27JUN2021. Applicant’s claim for the benefit of prior-filed application is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 29APR2024 and 12MAR2026 is/are acknowledged and the references cited therein have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (Fig 3 and 4) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located in Fig 4, specifically the HCDR2 of the 1101 antibody, and the HCDR1 of the 1103 and 1104 antibody do not appear in Table 1 or in the sequence listing.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Claim Objections
Claims 1-2 and 8 are objected to because of the following informalities:
Claims 1 and 2 contain the acronyms “Unc5B” in the last line of the claims. While acronyms are permissible as shorthand in the claims, the first recitation of the term should include the full recitation followed by the acronym in parentheses.
Claim 8 contains a typographical error: The “and” between “…LCDR3 comprises” and “amino acid sequence….” should be corrected appropriately.
Appropriate correction is required.
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 7, 13, and 17-20 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 7, 13, and 17-20 recite closed Markush group language “selected from the group” and also recite open language “comprising.” In this instance, it is unclear how the scope of claims 7, 13, and 17-20 allow for additional unrecited elements from the selected group. One of ordinary skill in the art would not be reasonably apprised of the scope of the patent protection sought with regard to the VH or VL sequences. Examiner notes that if claims were amended to:
“selected from the group consisting of SEQ ID NOs: …., and ….” or
“…comprising [the] amino acid sequence of SEQ ID NOs:…-…;” would obviate the rejection.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 13 and 17 recite the broad recitation at least 80% identity, and the claim also recite at least 99% identity which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 13 recites “The method of claim 1, wherein at least one of the following applies:…” and further recites the open language “comprising,” which does not exclude additional unrecited elements and also recites the closed language “consisting of,” which does not allow for additional unrecited elements (see MPEP § 2111.03). Therefore, it is unclear how the scope of claim 13 allows for additional unrecited elements and how they can also exclude additional unrecited elements. One of ordinary skill in the art would not be reasonably apprised of the scope of patent protection sought. For example, it is unclear in regards to claim 13 which recites “…comprising the VH of SEQ ID NOs: 43-52” or “…consisting of the VH selected from the group of SEQ ID NOs: 43, 44, 45, 46, 47, 48, 49, 50, 51, and 52….” if the patent protection sought is limited to i) the full-length of SEQ ID NOs: 43-52 with or without amino acid residues at either or both ends (i.e., comprising), or ii) the full-length of SEQ ID NOs: 43-52 and nothing more or less (i.e., consisting of).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In this instance, claim 8 recites “The method of claim 1, wherein the binding polypeptide binds an Uncoordinated 5B (Unc5B) protein.” However, the method of claim 1, recites “…an epitope of human, mouse, or rat Unc5B extracellular domain” which is considered a specific region of the Unc5B protein from human, mouse, or rat species rather than anywhere on the Unc5B protein from any species (i.e., claim 8 fails to further limit claim 1 upon which it depends). Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-13 and 17-22 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 enablement requirement. The claim(s) 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.
In the instance of claim 1, the nature of the invention drawn to a method for inducing permeability in the blood brain barrier in essentially any subject, comprising administering to the subject an effective amount of essentially any isolated polypeptide comprising an antigen-binding domain that specifically binds to an epitope of [the] human, mouse, or rat Unc5B extracellular domain, is not fully enabled.
With regards to claim 1, as presently written claim 1 is not fully enabled because:
i) The necessity of inducing permeability to the blood brain barrier in essentially any subject is unclear because the specification teaches that the BBB protects the brain from toxins and pathogens, and maintains homeostasis and proper function of the CNS (p 1, lines 20-21 of the originally filed specification). Although the specification goes on to state that the BBB impedes treatment of CNS pathologies because many drugs injected into the circulation cannot reach their targets behind the BBB and therefore the ability to open the BBB on demand and to restore its integrity when damaged has long been the holy grail of therapeutics (p 1, lines 22-25), the limitations from the specification are not read into the claims. Furthermore, the specification only teaches full-length IgG anti-Unc5B antibodies (i.e., specifically paired HC and LC) (see Fig 3).
ii) It should be pointed out, with regard to antibodies that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway, et al., Immunobiology: The Immune System in Health and Disease, 5th edition, 2001, section 3.6).
-AND-
iii) Furthermore, it is understood that knowledge of a given antigen (for instance a specific epitope of Unc5B) provides no information concerning the sequence/structure of antibodies that bind the given antigen. Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies.
Therefore the implementation of the invention in view of the unclear nature (i.e., the subject to which the antibody is to be administered), the lack of working examples which support anything other than a full-length IgG anti-Unc5b antibody of specific six nondegenerate CDRs, and the level of predictability in the art, would require undue experimentation for one of ordinary skill in the art to use the invention as presently claimed. Claims 7-13 and 17-21 are also rejected since they depend upon claim 1, but do not remedy this deficiency.
In claim 7, the specification supports the development of 10 full-length IgG anti-Unc5B antibodies, each of which have six specifically defined nondegenerate CDR sequences (Fig 3 and 4). Of the 10 antibodies, only four induced permeability in two difference cell lines and one decreased permeability (i.e., antibody clone 1097 comprising SEQ ID NOs: 1, 2, 5 15, 21, and 26). Therefore, while being enabling for the anti-Unc5B antibody comprising:
i) a HC which comprises the HCDR1-3 sequences of SEQ ID NOs: 13, 20, and 25 and a LC which comprises the LCDR1-3 sequences of SEQ ID NOs:1, 2, and 3;
ii) a HC which comprises the HCDR1-3 sequences of SEQ ID NOs: 18, 21, and 31 and a LC which comprises the LCDR1-3 sequences of SEQ ID NOs:1, 2, and 10;
iii) a HC which comprises the HCDR1-3 sequences of SEQ ID NOs: FNISYYSIHW, 23, and 32 and a LC which comprises the LCDR1-3 sequences of SEQ ID NOs:1, 2, and 11; or
iv) a HC which comprises the HCDR1-3 sequences of SEQ ID NOs: FNISYYSIHW, 24, and 32 and a LC which comprises the LCDR1-3 sequences of SEQ ID NOs:1, 2, and 12; does not reasonably provide enablement for more. Examiner notes that the amino acid sequence of FNISYYSIHW is addressed in the amino acid sequence deficiency supra and would require a SEQ ID NO for inclusion in the claim.
Claim 10 recites the method of claim 9 (i.e., the binding polypeptide comprises an antibody or an antigen-binding fragment thereof), wherein the antigen-binding fragment is selected from the group consisting of a Fab, a single-chain variable fragment, and a single-domain antibody and is not fully enabled. In the instance of single domain antibodies, the formation of an intact antigen-binding site requires the association of three CDRs or CDR1, HV2, HV4, and CDR3 for VHH or VNARs, respectively (rather than the six present in conventional VH/VL antibodies (Henry, et al., MAbs, 2018, 10, 815-826, see entire document). Gordon teaches that the CDR3 loop contributes most to sdAb-antigen binding specificity and is typically longer than the CDR-H3 loop of a conventional antibody (Gordon, et al., Front Immunol, 2023, 14, 1-18, see entire document). Asaadi, et al., teach that the sdAbs evolved with an extra disulfide bond between CDR1, CDR2, or FR2, which in addition to the other structural features of a sdAb increases paratope diversity and allows for a wide variety of geometrical loop structures that deviate fundamentally from the canonical loop structures defined for conventional antibodies (Asaadi, et al., Biomarker Res, 2021, 9, 1-20, see entire document). Therefore, the specific combination of CDRs 1-3 or CDR1-HV2-HV4-CDR3 affects structure within the sdAb and specific antigen binding. Thus, based upon the prior art, skilled artisans would reasonably understand that it is the organization of the three CDRs or CDR1-HV2-HV4-CDR3 in a specific combination, in a single domain antibody, which gives rise to the functional property of antigen binding to in this instance, Unc5B.
Claims 13 and 17-20 are not fully enabled because the specification teaches full-length anti-Unc5B IgG antibodies comprising specifically paired heavy and light chains (see Fig 3), and does not teach VH only antibodies (i.e., see discussion supra regarding sdAb) or VL only antibodies. Furthermore, the sequences that are claimed comprise the full-length HC or LC, rather than the claimed VH or VL, respectively, and therefore it is unclear whether in the instance of % identity of claims 13 and 17, whether the identity applies to the VH or VL or the HC or LC, respectively. Furthermore, there is no evidence that an antigen binding region comprising only the VL region of claims 17-20 would effectively bind to Unc5B without undue experimentation to determine the VH region.
In the instance of claim 2, the nature of the invention drawn to a method of increasing brain penetration of a therapeutic agent in essentially any subject, the method comprising administering to the subject an effective amount of essentially any isolated polypeptide comprising an antigen-binding domain that specifically binds to an epitope of [the] human, mouse, or rat Unc5B extracellular domain, wherein the subject is further administered essentially any therapeutic agent is not fully enabled.
With regards to claim 2, as presently written claim 2 is not fully enabled because:
i) The specification teaches the BBB impedes treatment of CNS pathologies because many drugs injected into the circulation cannot reach their targets behind the BBB and utilization of antibodies targeting Unc5B would allow more effective therapeutic targeting of CNS tissues (i.e., a specific disease or pathology is being targeted) (p 1, lines 22-23 and lines 27-29). Furthermore, the specification teaches the utilization of specific anti-Unc5B antibodies which are able to induce BBB permeability for dyes and/or compounds of < 40 kDa molecular weight such as cadaverine, nanobodies of 12-15 kDa, dextran tracers of 40 kDa, or brain-derived neurotrophic factor (BDNF), which is approximately 27-28 kDa (i.e., specifically sized compounds, which are therapeutically applied to treating neurologic or neuropsychiatric disorders) (Example 3). With regards to the anti-Unc5B antibodies, the specification teaches that antibodies 1095, 1102, 1103, and 1104 were able to induce permeability in both cell lines, whereas antibody 1097 decreased basal permeability (i.e., not all anti-Unc5B antibodies are effective in increasing the BBB permeability) (p 59, lines 15-18). Additionally, only full-length IgG anti-Unc5B antibodies are supported by the specification (i.e., specifically paired HC and LC) (see Fig 3).
ii) See discussion supra regarding an antibody comprising six nondegenerate CDRs.
iii) The literature teaches that increasing brain penetration of certain therapeutic agents results in unwanted neurologic side effects.
a) First-generation antihistamines are effective H2-receptor antagonists, but they are also lipophilic and readily cross the BBB causing considerable sedation and/or cognitive function/psychomotor performance impairment, resulting in the development of newer generation antihistamines that were designed to be effective H2-receptor antagonists and do not cross the BBB (Ansotegui, et al., Curr Med Res Opin, 2024, 40, 1297-1309, see p 1298, col 1, first full paragraph).
b) Chemotherapy drugs can induce severe side effects in the central nervous system (CNS), leading to conditions like “chemobrain.” For example, chemotherapeutic agents can cross the BBB, directly affecting microglia and astrocytes, inducing pathological gliosis and neuroinflammation. These drugs, including cisplatin and cyclophosphamide (i.e., indiscriminate between healthy and cancerous cells), can impair neurogenesis and disrupt neural network dynamics. (Tumanyan, OncoDaily, 2025, 1-12, see How often do cancer patients experience chemobrain? section).
In this instance not all therapeutics are fully enabled as certain therapies result in adverse effects and/or neurotoxicity. iv) See discussion supra regarding claiming an antibody by epitope.
-AND-
v) The implementation of the invention in view of the unclear nature (i.e., the targeted disease and therefore therapeutic used), the lack of specific direction provided by the specification and working examples, and the level of predictability in the art, would require undue experimentation for one of ordinary skill in the art to use the invention as presently claimed. Claims 3-6 and 22 are also rejected since they depend upon claim 2, but do not remedy this deficiency.
Therefore, while being enabling for:
“A method for the treatment of a brain-related disease or disorder comprising administering a therapeutically effective amount of an Unc5B antibody and administering a therapeutically effective amount of a therapeutic targeting a brain-related disease or disorder to a subject in need thereof,
wherein the Unc5B antibody comprises:
i) a HC which comprises the HCDR1-3 sequences of SEQ ID NOs: 13, 20, and 25 and a LC which comprises the LCDR1-3 sequences of SEQ ID NOs:1, 2, and 3;
ii) a HC which comprises the HCDR1-3 sequences of SEQ ID NOs: 18, 21, and 31 and a LC which comprises the LCDR1-3 sequences of SEQ ID NOs:1, 2, and 10;
iii) a HC which comprises the HCDR1-3 sequences of SEQ ID NOs: FNISYYSIHW, 23, and 32 and a LC which comprises the LCDR1-3 sequences of SEQ ID NOs:1, 2, and 11; or
iv) a HC which comprises the HCDR1-3 sequences of SEQ ID NOs: FNISYYSIHW, 24, and 32 and a LC which comprises the LCDR1-3 sequences of SEQ ID NOs:1, 2, and 12; and
wherein the therapeutic targeting a brain-related disease or disorder comprises a compound of < 40 kDa molecular weight;” does not reasonably provide enablement for more. Examiner notes that the amino acid sequence of FNISYYSIHW is addressed in the amino acid sequence deficiency supra and would require a SEQ ID NO for inclusion in the claim.
Claims 4 and 5 are not fully enabled because the literature teaches that treatment provides increased control over a disease in patients that already have the disease (i.e., brain-related disease or disorder comprising cancer), prevention reduces the probability of a disease-free patient from getting the disease (i.e., brain-related disease or disorder comprising cancer), and that while certain chemotherapeutic agents have shown clinical promise to treat a brain-related disease or disorder comprising cancer, evidence for prevention of the disease is not discussed. Specifically, it is well known in the art, that cancer treatment refers to the use of interventions (e.g., chemotherapy, radiation therapy, surgery, immunotherapy, or a combination thereof) to eliminate or control cancer cells that are already present in the body; whereas cancer prevention is an action taken (e.g., changes in diet and lifestyle, screening, chemoprevention) to lower the chance of getting cancer (see entire documents: NIH-NCI, Cancer Prevention Overview, 2023; Mayo Clinic, Cancer Treatment, 2024; and NCFR ,Cancer Intervention vs Prevention: What does it Mean?, 2024). The prior art does not teach preventative uses of chemotherapy for a brain-related disease or disorder comprising cancer.
Claim 6 is not fully enabled. As discussed supra, several therapeutic agents are known to cause neurotoxicity and therefore increasing brain penetration of such an agent is likely to cause significant adverse effects such as headaches, vision loss, speech difficulty, seizures and/or encephalopathy for the subject. In this instance, Magge, et al., teach that several of the therapeutic agents listed in claim 6 (e.g., asparaginase, busulfan, cisplatin, gemcitabine, hydroxyurea, methotrexate, vincristine, etc.) are known to induce neurotoxicity resulting in a range of adverse CNS effects (Magge, et al., Blood Rev, 2014, 29, 93-100, see Table 5). Therefore, it would require a specific case-by-case evaluation to determine whether the efficacy outweighs the neurotoxic side effects which would likely be amplified by increasing brain penetration of these therapies.
Written Description
Claims 1-13 and 17-22 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.
Scope of the claimed genus:
Applicant has broadly claimed a method for inducing permeability in the blood brain barrier in essentially any subject, comprising administering to the subject an effective amount of essentially any isolated polypeptide comprising an antigen-binding domain that specifically binds to an epitope of [the] human, mouse, or rat Unc5B extracellular domain or a method of increasing brain penetration of a therapeutic agent in essentially any subject, the method comprising administering to the subject an effective amount of essentially any isolated polypeptide comprising an antigen-binding domain that specifically binds to an epitope of [the] human, mouse, or rat Unc5B extracellular domain, wherein the subject is further administered essentially any therapeutic agent. In this instance, the broadest claims define the isolated polypeptide comprising an antigen-binding domain by the function of binding Unc5B and inducing permeability in the BBB or increasing brain penetration of a therapeutic agent. No claims recite any specific or particular structure of the isolated polypeptide comprising an antigen-binding domain that gives rise to the specific use functions upon administration to the subject, apart from claims 13 and 17-20, which only partially define a structure. Claim 13 only provides a % identity to the VH as a part of the HC without any mention of the VL/LC; Claim 17 only provides % identity to the VL as a part of the LC without any mention of the VH/HC; and Claims 18-20 provides information about the VL as part of the LC without any mention of the VH/HC (i.e., Claims 13 and 17-20 fail to recite the full structure of the isolated polypeptide comprising an antigen-binding region that functions to bind to the human, mouse, or rat Unc5B extracellular domain). Thus, it is clear that the claims encompass antibodies with potential CDR mutations and/or substitutions relative to the claimed sequences, but neither the claims nor the specification define where the mutation can occur that will maintain the claimed specificity.
State of the relevant art:
Artisans are well aware that knowledge of a given antigen (for instance a specific epitope of human, mouse, or rat Unc5B extracellular domain) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well (Edwards, et al., J Mol Biol, 2003, 334, 103-118, see entire document). Goel et al. disclose the synthesis of three monoclonal antibodies that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (Goel, et al., J Immunol, 2004, 173, 7358-7367, see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., J Biol Chem, 1995, 270, 18067-18076, see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably represent the breadth of the genus of antibodies that bind the given antigen in the instant application.
With regard to antibodies, it should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway, et al., Immunobiology: The Immune System in Health and Disease, 5th edition, 2001, section 3.6). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff, et al., PNAS, 1982, 79, 1979-1983 see entire document, particularly the abstract and the middle of the left column of p 1982). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
For example, below is an alignment of two VH domains of anti-Unc5B extracellular domain antibodies (i.e., SEQ ID NOs: 25 and 28) disclosed in US 2010/0221262 A1 (Koch, et al., 02SEP2010) (¶0016, ¶0311, and ¶0338). Despite sharing the same immunogen (i.e., the extracellular domain of Unc5B) the resulting antibodies share little similarity at the sequence level, particularly for HCDR3:
PNG
media_image1.png
233
631
media_image1.png
Greyscale
Accordingly, the skilled artisan would be unable to envisage the isolated polypeptide comprising an antigen-binding region that binds to the human, mouse, or rat Unc5B extracellular domain thereof and induces BBB permeability or increases brain penetration of a therapeutic a priori given the current state of the antibody arts.
Description of representative species in the specification:
MPEP § 2163 states that “a representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
To support such broad claims, the specification teaches 10 anti-Unc5B antibody clones having six nondegenerate CDRs and further defined by their HC and LC pairs (see Fig 3 and 4). However, given the immense breadth of the claims and the depth and diversity of the antibody repertoire as described above, such a disclosure would not reasonably be considered representative of the genus: an antibody, which is only described by its binding target.
Identifying characteristics and structure/function correlation:
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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.
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017). In Amgen v. Sanofi, the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e., the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it. As such, knowledge of where an antibody binds provides no information as to what such an antibody necessarily looks like (i.e., its primary amino acid structure).
It should also be noted that the USPTO has released a Memo on the Clarification of Written Description Guidance For Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See https://www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. This Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies and states: “In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.” Further, the courts have indicated that the enablement and written description requirements of 35 USC 112 are separable as can be seen in for example Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111.
To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed human, mouse, or rat Unc5B ECD binding activity and inducing permeability in the BBB or increasing brain penetration of a therapeutic agent.
The specification discloses 10 antibody clones having six nondegenerate CDRs, of which four antibody clones (i.e., 1095, 1102, 1103, and 1104) were able to induce permeability in both cell lines, whereas antibody clone 1097 decreased basal permeability (p 59, lines 15-18). Therefore, although the 1097 clone binds Unc5B it does not fulfill the secondary function of inducing BBB permeability or increasing brain penetration of a therapeutic agent.
Claim analysis:
In this instance, the prior art supports six nondegenerate CDRs to define the structure of an antibody that functions to bind a particular epitope, e.g., the human, mouse, or rat Unc5B ECD and the specification supports that not all anti-Unc5B antibody clones function to induce BBB permeability or increase brain penetration of a therapeutic. Therefore, as presently written, the claimed broad genus of an antigen-binding domain that binds the human, mouse, or rat Unc5B ECD and induces BBB permeability or increases brain penetration of a therapeutic (i.e., claims 1 and 2) lacks adequate written description because there does not appear to be any correlation between the structure of the isolated polypeptide comprising an antigen-binding domain (i.e., an antibody) and the ability to bind the ECD of human, mouse, or rat Unc5B and induce BBB permeability or increase brain penetration of a therapeutic.
Claims 13 and 17 allow for mutations within the CDR regions of the antibody. The specification does not provide guidance as to how to identify antibodies that express variations of the CDRs and maintain the claimed functions. Claims 13 and 17 disclose the sequence of the antibody variable regions and allow for 80-99% variation from the disclosed HC or LC sequence, but do not offer guidance on what regions of the variable regions the sequences may differ and still function as claimed. Because these claims allow for mutations within the CDR regions of the antibody, one of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as is claimed. There is no disclosure of a correlation between structure and function that would allow those of skill in the art to recognize other members of the claimed genus from the disclosure.
Claims 18-20 provide the structure for the VL of the LC without providing the structure of the VH or the HC and the specification does not provide evidence of a VL only polypeptide which is able to effectively bind the ECD of Unc5B and effectively induce permeability or increase brain penetration of a therapeutic agent.
Therefore, the specification provides neither a representative number of the encompassed antibodies, nor does it provide a descriptive of structural features that are common to the encompassed antibodies. Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the artisan cannot envision the detailed structure of the encompassed antibodies and non-antibody proteins and therefore Applicant was not in possession of the instant claimed invention.
Logically, if Applicant was not in possession of the agent which is being administered, applicant also was not in possession of methods of administering such reagents at the time the instant application was filed.
Claim Rejections - 35 USC § 103
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.
Claims 1-6, 8-12, and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over US 2010/0221262 A1 (Koch, et al., 02SEP2010), herein referred to as “’262” and in view of de Faria, Jr., et al., (bioRxiv, 10SEP2020), herein referred to as “de Faria.”
‘262 teaches anti-Unc5B antibodies and fragments thereof, which are able to bind to the ECD of human Unc5B and pharmaceutical compositions thereof comprising the anti-Unc5b antibodies with a pharmaceutically acceptable carrier or comprising an admixture with one or more additional agents selected from a cytotoxic agent, a chemotherapeutic agent, etc., which are administered to inhibit binding of Netrin-1 protein to Unc5B protein (¶0016-0017, ¶0019-0020, ¶0311, and ¶0338).
However, they do not teach: inducing permeability in the BBB or increasing brain penetration of a therapeutic agent.
Nevertheless, de Faria teaches that the extracellular region of Unc5 homologues are composed of two Ig domains which bind netrin-1 and that netrin-1 made by vascular endothelial cells regulates tight junction protein levels to control BBB permeability (see abstract and discussion section). In this work, de Faria teaches that in vivo Unc5B knockout resulted in reduced expression of tight junction proteins suggesting that Unc5B-mediated netrin-1 signaling regulates tight junctions and therefore the absence of Unc5B binding to netrin-1 could contribute to the disruption of the tight junctions (see discussion section).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the administration of anti-Unc5B antibodies to inhibit binding of Netrin-1 protein to Unc5B protein disclosed by ‘262 for affecting tight junctions in the BBB as disclosed by de Faria because by blocking Unc5b binding to netrin-1, the expression of tight junction proteins are reduced resulting in disruption of the tight junction of the BBB. One would have been motivated to do so, given the teachings of ‘262 that the anti-Unc5B antibodies were to be used to block the netrin-1 and Unc5B interaction. There would have been a reasonable expectation of success, given the knowledge that inhibiting the Unc5B-mediated nectin-1 signaling resulted in reduced expression of tight junction proteins and would therefore result in disruption of the tight junctions such as those in the BBB (i.e., induce BBB permeability).
Furthermore, although ‘262 is silent with regard to the anti-Unc5B antibodies inducing permeability in the BBB or increasing brain penetration of a therapeutic agent in a subject as a result of binding the ECD of Unc5B in claims 1-2, it is noted that a compound and all of its properties are inseparable; they are one and the same thing (see In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) and MPEP §2112.01). Therefore, in the absence of evidence to the contrary, the anti-Unc5B antibodies taught by ‘262 would have the claimed properties recited in claims 1-2.
Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time of filing.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at (571)272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
Prosecution Insights