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 .
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 - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because the “Sequence Listing XML,” as a separate part of the disclosure, is defective, damaged or unreadable.
The sequences of SEQ ID NOs: 222-247 in the Sequence Listing in Computer Readable Format filed May 18, 2023 are Defective and cannot be read or retrieved.
Required response - Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above submitted in accordance with either item 1. or 2.; together with
o A statement that identifies the location of all additions, deletions or replacements of sequence information relative to the replaced “Sequence Listing XML” as required by 37 CFR 1.835(b)(3);
o A statement that indicates support for the replacement “Sequence Listing XML” in the application, as filed, as required by 37 CFR 1.835(b)(4); and
o A statement that the replacement “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(b)(5).
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125, inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
DETAILED ACTION
Status of Application/Election/Restrictions
Applicant’s election of Group I (claims 1-2, 5-7, 10, 13, 19, 21-22, 29, 34-36, 39-41, 43-44, 61, 66-68, 72, 79 and 85-86), anti-Gal3 antibody TB006, SEQ ID NOs: 31, 72, 113, 171, 222, 249, 298, 375, 449, 496, 540 and 622, and stroke in the reply filed on September 18, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 3-4, 8-9, 11-12, 14-18, 20, 23-28, 30-33, 37-38, 42, 45-60, 62-65, 69-71, 73-78, 80-84 and 87-89 are canceled. Claims 1-2, 5-7, 10, 13, 19, 21-22, 29, 34-36, 39-41, 43-44, 61, 66-68, 72,79, 85-86 and 90-91 are pending in this application. Claims 90-91 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Claims 35-36, 39-41, 43-44, 61, 66-68, 72 and 79 are also withdrawn from further consideration because of non-elected species. Election was treated as without traverse in the reply filed on September 18, 2025.
Claims 1-2, 5-7, 10, 13, 19, 21-22, 29, 34 and 85-86 are under examination with respect to anti-Gal3 antibody TB006, SEQ ID NOs: 31, 72, 113, 171, 222, 249, 298, 375, 449, 496, 540 and 622, and stroke in this office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings/figures 1-9 and 13-17 are objected to because sequence listings included in the specification must not be duplicated in the drawings. See 37 C.F.R. §1.58(a) and §1.83(a). Appropriate correction is required.
See MPEP § 608.02-I Drawing requirements
If the specification includes a sequence listing or a table, such a sequence listing or table is not permitted to be reprinted in the drawings. 37 CFR 1.83(a) and 1.58(a). If a sequence listing as shown in the drawings has more information than is otherwise contained in the specification, the sequence listing could be included in the specification and the drawings. Applications filed under 35 U.S.C. 371 are excluded from the prohibition from having the same tables and sequence listings in both the description portion of the specification and drawings.
Specification
The disclosure is objected to because of the following informalities: The use of the term ”nanobody (p.12, [0075])”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term 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. Appropriate correction is required.
Claim Objections
Claims 35-36, 39-41, 43-44, 61, 66-68, 72, 79 and 90-91 are objected to because of the following informalities: the status of the claims 35-36, 39-41, 43-44, 61, 66-68, 72, 79 and 90-91 is incorrect because these claims are withdrawn from consideration. Appropriate correction is required.
See MPEP 714 & 37 CFR 1.121.
“In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).”
Claims 1 and 29 are objected to because of the following informalities: the recitation “Gal3” in claim 1 and the recitations “TB001, TB006, 12G5.D7, 13A12.2E5, 14H10.2C9, 15F10.2D6, 19B5.2E6,…….20H5.A3-VH6VL1, 20H5.A3-VH6VL3” recited in claim 29 are not unique or common abbreviations in the art. Applicants are required to spell out the limitations “TB001, TB006, 12G5.D7, 13A12.2E5, 14H10.2C9, 15F10.2D6, 19B5.2E6,…….20H5.A3-VH6VL1, 20H5.A3-VH6VL3” recited in claim 29 at the first usage. Appropriate correction is required.
Improper Markush Grouping
11. Claim 29 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush grouping of different anti-Gal3 antibodies “TB001, TB006, 12G5.D7, 13A12.2E5, 14H10.2C9, 15F10.2D6, 19B5.2E6,…….20H5.A3-VH6VL1, 20H5.A3-VH6VL3” recited in claim 29 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The recited alternative species do not share a single structural similarity, as each species of anti-Gal3 antibody has a different chemical structure because it comprises different amino acid sequences for a heavy chain (HC), a light chain HC), a heavy chain variable region (HCVR), a light chain variable region (HCVR), heavy chain CDRs1-3 (HCDRs1-3) and light chain CDRs1-3 (LCDRs1-3). Each antibody has a different binding activity to different epitopes. Thus, the antibodies do not share a single structural similarity or biological activity. Accordingly, while the different antibodies are asserted to have the property of being correlated with a neurological or movement disorder or an altered susceptibility thereto, they do not share a single structural similarity essential to this activity. See MPEP § 706.03(y).
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
12. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 5-7, 10, 13, 19, 21-22, 29, 34 and 85-86 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 pre-AIA the applicant regards as the invention.
Claims 1-2, 5-7, 10, 13, 19, 21-22, 29, 34 and 85-86 are indefinite because:
i. The term “reducing”, “reduce” or “reduction” in claims 1, 10, 19 and 21 or the term “elevation” in claim 10 is a relative term which renders the claim indefinite. The term “reducing”, “reduce”, “reduction” or “elevation” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Applicant fails to set forth the metes and bounds of what is encompassed within the definition of “reducing”, “reduce”, “reduction” or “elevation”. Since the metes and bounds are unknown, a skilled artisan cannot envision what would be considered as ““reducing/reduce loss of locomotor function”, “reduction in levels” or “elevation of levels” expect to optimize presentation as recited in the claim. Thus, the claims are indefinite.
ii. Regarding claim 29, the terms “TB001, TB006, 12G5.D7, 13A12.2E5, 14H10.2C9, 15F10.2D6, 19B5.2E6,…….20H5.A3-VH6VL1, 20H5.A3-VH6VL3” are recited in the claim without a reference to a precise amino acid sequence identified by a proper SEQ ID NO: or providing a full name for abbreviated names. Without identification of property or combination of properties which are unique to and, therefore, definitive of the instant recitations, the metes and bounds of the claims remain undetermined. Further, the use of laboratory designations only to identify a particular molecule renders the claims indefinite because different laboratories may use the same laboratory designations to define completely distinct molecules. The rejection can be obviated by amending the claims to specifically and uniquely identify “TB001, TB006, 12G5.D7, 13A12.2E5, 14H10.2C9, 15F10.2D6, 19B5.2E6,…….20H5.A3-VH6VL1, 20H5.A3-VH6VL3” , for example, by SEQ ID NO: and function of the “TB001, TB006, 12G5.D7, 13A12.2E5, 14H10.2C9, 15F10.2D6, 19B5.2E6,…….20H5.A3-VH6VL1, 20H5.A3-VH6VL3” recited in claim 29.
iii. Claims 85-86 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: no subject for the step of administering and there is no purpose, or use or preamble for the step of administering 5 unit doses of an anti-Gal3 antibody.
iv. The rest of claims are indefinite as depending from an indefinite claim.
Claim Rejections - 35 USC § 112
13. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 5-7, 10, 13, 19, 21-22, 29, 34 and 85-86 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 reducing loss of locomotor activity, increasing latency to fall and distance traveled, reducing microhemorrhage, reducing activated microglia and reducing activated astrocytes in an animal model of intracerebral hemorrhage (ICH) stroke after treatment with mTB001 as compared to wild type control mice, does not reasonably provide enablement for a method for inhibiting, reducing, preventing and/or treating stroke in a subject in need thereof comprising administering a structurally and functionally undefined anti-Gal3 antibody or binding fragment thereof to the subject as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. In addition, the specification does not enable the invention of claims 1-2, 5-7, 10, 13, 19, 21-22, 29 and 34 that is directed to a method of prevention and curing.
“There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is ‘undue’. These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)”. See MPEP § 2164.01.
Claims 1-2, 5-7, 10, 13, 19, 21-22, 29 and 34 are drawn to methods for inhibiting, reducing, preventing and/or treating stroke in a subject in need thereof, comprising administering an anti-Gal3 antibody or binding fragment thereof to the subject, thereby i inhibiting, reducing, preventing and/or treating stroke.
Claims 85-86 are drawn to a method comprising administering 5unit doses of an anti-Gal3 antibody or binding fragment thereof, wherein each unit dose comprise 1000 mg or about 1000 mg of the anti-Gal3 antibody or binding fragment thereof, wherein the unit doses are administered every 7 days or about 7 days, and wherein each unit dose is administered over the course of 1 hour or about 1hour.
The claims encompass methods preventing or treating stroke using a structurally and functionally undefined anti-Gal3 antibody or binding fragment thereof in view of paragraph [0096] of instant specification (based on published application). The method of claims 85-86 provides no utility by administering 5-unit doses of an anti-Gal3 antibody or binding fragment thereof, wherein the unit doses are administered every 7 days or about 7 days, and wherein each unit dose is administered over an hour or about an hour.
The instant invention is based on findings that intraperitoneal administration of mTB001 at 10mg/kg for 8 doses twice in a week to an animal model of intracerebral hemorrhage (ICH) stroke resulted in reducing loss of locomotor activity and increasing latency to fall and distance traveled (figures 23A-D), reducing microhemorrhage based on Prussian Blue-positive area (Figures 24A-D), reducing activated microglia and astrocytes based on 1ba1 positive immunostaining (Figures 25A-B) in the animal model of ICH stroke treated with mTB001 compared to wild type control mice.
Applicant extrapolates the above findings to the claimed methods of preventing or treating stroke using a structurally and functionally undefined anti-Gal3 antibody or binding fragment thereof.
First, Applicant is not enabled for a method of preventing a person from getting stroke. Neither the specification nor the prior art provides guidance as to how to prevent a person from getting stroke including ICH caused by all possible mechanisms before the stroke happens. Any individual has a potential to develop stroke caused by all possible mechanisms. Applicant fails to teach how to identify or predict when and which person would be susceptible to such a disease or developing the disease, and predict when the person would need administration of the claimed anti-Gal3 antibody to prevent the disease from happening before the disease occurs. Neither the specification nor the prior art teaches that administration of the claimed anti-Gal3 antibody can prevent a person from getting stroke caused by all possible mechanisms. The causes of stroke including ICH could be due to high blood pressure and protein build up in artery with aging AD, which is genetic and is a natural process. It is impossible to prevent a person from getting or developing stroke caused by results of a natural process. The specification fails to provide sufficient guidance to enable one of skill in the art to practice the invention as it pertains to a method of prevention. Further, Applicant fails to provide specific guidance as to what specific amount of the claimed anti-Gal3 can be used and thus would be effective to prevent stroke caused by all possible mechanisms. Thus, a skilled artisan cannot contemplate a right amount to prevent the disease or to prevent a person from getting the disease or cure the disease.
Second, based on the specification and the prior art, Applicant is enabled for reducing loss of locomotor activity and increasing latency to fall and distance traveled (figures 23A-D), reducing microhemorrhage based on Prussian Blue-positive area (Figures 24A-D), reducing activated microglia and astrocytes based on 1ba1 positive immunostaining (Figures 25A-B) in an animal model of ICH stroke treated with mTB001 compared to wild type control mice by intraperitoneal administration of mTB001 at 10mg/kg for 8 doses twice in a week to the animal model of intracerebral hemorrhage (ICH) stroke.
However, the claims are not limited to the mTB001 anti-Gal3 antibody and the method set forth above but also encompass using structurally and functionally undefined anti-Gal3 antibodies including elected TB006 anti-Gal3 antibody (corresponding sequences: SEQ ID NOs: 31, 72 and 113, and SEQ ID NOs:171, 222 and 249 for HCDRs1-3 and LCDRs1-3 respectively; SEQ ID NOs: 298 and 375 for VH and VL respectively; SEQ ID NOs: 449 and 496 for HC and LC respectively; and SEQ ID NOs: 540 and 622 VH and VL DNA sequences).
The specification provides insufficient guidance to enable one of skill in the art to practice the full scope of the claimed invention without undue experimentation because the specification provides no well-established structural and functional relationship or correlation between the claimed Gal3 antibody including TB006 (elected) and the mTB001 anti-Gal3 antibody in recovering locomotor activity deficit and increasing latency to fall and distance traveled, reducing microhemorrhage based on Prussian Blue-positive area, reducing activated microglia and astrocytes based on 1ba1 positive immunostaining in the animal model of ICH stroke treated with mTB001 compared to wild type control mice or even treating or preventing stroke.
Allumette-Hebert et al. (J. Neurosci. 2012; 32:10383-10395) teach that disruption of the galectin-3 gene in a galectin-3 knock-out mouse (Gal-3KO) resulted in significantly altering microglia activation and induces ~4-fold decrease in microglia proliferation and that defective microglia activation/proliferation was further associated with significant “increase” in the size of ischemic lesion, ~2-fold increase in the number of apoptotic neurons, and a marked deregulation of the IGF-1 levels, suggesting that Galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury (see abstract). It is unpredictable whether all the claimed Gal3 antibodies have the same activity as mTB001 in reducing loss of locomotor activity and increasing latency to fall and distance traveled (figures 23A-D), reducing microhemorrhage based on Prussian Blue-positive area (Figures 24A-D), reducing activated microglia and astrocytes based on 1ba1 positive immunostaining (Figures 25A-B) in the animal model of ICH stroke treated with mTB001 compared to wild type control mice.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs 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. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. MacCallum et al. (J. Mol. Biol.,1996; 262: 732-745) teaches that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see p. 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). Pascalis et al. (The Journal of Immunology, 2002; 169: 3076-3084) teaches that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.) and that although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site because although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.; Casset et al., BBRC, 2003; 307: 198-205). Vajdos et al. (J. Mol. Biol. 2002; 320: 415-428) also teaches that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.). Holm et al.(Mol. Immunol., 2007; 44: 1075-1084) teaches that although residues in the CDR3 of the heavy chain were involved in antigen binding, unexpectedly a residue in CDR2 of the light chain was also involved (abstract). Chen et al. (J. Mol. Bio., 1999; 293: 865-881) teaches that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu et al. (J. Mol. Biol., 1999; 294:151-162) teaches that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation. These references teach that an antibody with the claimed binding activity or features must comprise all 6 CDRs with defined sequences or structures in order to maintain the claimed antigen binding specificity and affinity and activity.
The specification also fails to teach what other sequences must be conserved in order to maintain the activity as mTB001 in the animal model of ICH stroke because a single amino acid change on a molecule or protein can abolish the binding ability or activity of the molecule or protein. For example, a substitution of lysine residue by glutamic acid at position 118 of acidic fibroblast growth factor results in a substantial loss of its biological activity including the binding ability to heparin and its receptor (Burgess et al. J of Cell Bio. 1990, 111:2129-2138). Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would not immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active because conformation is dependent upon surrounding residues; i.e. substitution of non-essential residues can often destroy activity. In addition to a core determinant sequence, the protein-protein interaction also relies on the flanking or noncontiguous residues (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452). The optimal binding motif for a domain is not necessarily suitable for physiological or in vivo interaction. The predictive data always need to be validated by actual analyses in cells (see p. 445, the third column, second paragraph, Pawson et al. 2003, Science 300:445-452). Alaoui-lsmaili teaches that designing a mutein having predictable activities is difficult because of the complexity of the interactions between ligands and receptors (Alaoui-lsmaili et al., Cytokine Growth Factor Rev. 2009; 20:501-507). For example, given the complexity of BMP-BMP receptor interactions, it is difficult to design BMPs with improved affinity and/or specificity for one specific receptor. More importantly, predicting the in vivo biological activity of such altered BMPs remains a challenging undertaking (see p. 502, right col., 2th paragraph). Further, when multiple mutations are introduced, there is even less predictability because Guo et al. teaches that the effects of mutations on protein function are largely additive (see p. 9207, left col., 2th paragraph, Guo et al., PNAS 2004; 101:9205-9210). The specification fails to teach what other structures/amino acid sequences can or cannot not be included/changed in anti-Gal3 antibodies including elected TB006 in order to preserve the activity of mTB001 in reducing loss of locomotor activity and increasing latency to fall and distance traveled, reducing microhemorrhage based on Prussian Blue-positive area, reducing activated microglia and astrocytes based on 1ba1 positive immunostaining in the animal model of ICH stroke treated with mTB001 compared to wild type control mice or even in treating or preventing stroke. Thus, it is unpredictable whether TB006 or other Gal3 antibodies can be used in the claimed method of treating or preventing stroke, indicating undue experimentation is required by a skilled artisan to perform while practicing the claimed invention.
Therefore, in view of the breadth of the claims, the lack of guidance in the specification, the limited examples, the unpredictability of inventions, and the current status of the art, undue experimentation would be required by one of skill in the art to perform in order to practice the full scope of the claimed invention as it pertains to a method for treating or preventing stroke by the claimed anti-Gal3 antibody.
Claim Rejections - 35 USC § 112
14. Claims 1-2, 5-7, 10, 13, 19, 21-22, 29, 34 and 85-86 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.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claims 1-2, 5-7, 10, 13, 19, 21-22, 29, 34 and 85-86 encompass using a genus of structurally and functionally undefined anti-Gal3 antibody or a genus of binding fragment thereof for treating or preventing stroke.
Applicant has not disclosed sufficient species for the broad genus of anti-Gal3 antibodies or binding fragment thereof including TB006 antibody.
The specification only disclosed that intraperitoneal administration of mTB001 at 10mg/kg for 8 doses twice in a week to an animal model of intracerebral hemorrhage (ICH) stroke resulted in reducing loss of locomotor activity and increasing latency to fall and distance traveled (figures 23A-D), reducing microhemorrhage based on Prussian Blue-positive area (Figures 24A-D), reducing activated microglia and astrocytes based on 1ba1 positive immunostaining (Figures 25A-B) in the animal model of ICH stroke treated with mTB001 compared to wild type control mice.
However, the claims are not limited to the use of mTB001 set forth above but also encompass using a genus of structurally and functionally undefined anti-Gal3 antibodies for treating and preventing stroke.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. From the specification, Applicant is in possession of using mTB001 anti-Gal3 antibody for reducing loss of locomotor activity and increasing latency to fall and distance traveled, reducing microhemorrhage based on Prussian Blue-positive area, reducing activated microglia and astrocytes based on 1ba1 positive immunostaining in the animal model of ICH stroke treated with mTB001 compared to wild type control mice. However, Applicant is not in possession of using other structurally and functionally undefined anti-Gal3 antibody including TB006 for treating stroke or even preventing stroke because the specification fails to provide a well-established structural and functional relationship or correlation between the claimed genus of anti-Gal3 antibodies including TB006 and mTB001 anti-Gal3 antibody in reducing loss of locomotor activity and increasing latency to fall and distance traveled, reducing microhemorrhage based on Prussian Blue-positive area, reducing activated microglia and astrocytes based on 1ba1 positive immunostaining in the animal model of ICH stroke treated with mTB001 compared to wild type control mice.
The specification provides insufficient description as to what other common structures or sequences and features are required by the claimed genus of anti-Gal3 antibodies including TB006 in order to preserve the activity of mTB001 in reducing loss of locomotor activity and increasing latency to fall and distance traveled, reducing microhemorrhage based on Prussian Blue-positive area, reducing activated microglia and astrocytes based on 1ba1 positive immunostaining in the animal model of ICH stroke treated with mTB001 compared to wild type control mice or even in treating or preventing stroke.
Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to identify what other anti-Gal3 antibodies having the same activity as mTB001 might be. Since the common characteristics/features of other anti-Gal3 antibodies including elected TB006 are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of anti-Gal3 antibodies that can be used in the claimed for treating or preventing stroke.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “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).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of anti-Gal3 antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed methods have not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
Conclusion
15. NO CLAIM IS ALLOWED.
16. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
NCT05156827 (published 2022-07-26; a study to assess the efficacy, safety and pharmacokinetics of TB006 in participants with Acute ischemic Stroke (see p. 1) discloses a method of evaluating the efficacy, safety and pharmacokinetics of TB006 antibody in patients with acute ischemic stroke, wherein the patients will receive intravenous 3 infusion of 4000mg TB006 one every 28 days (Q28D) (p.6).
Mosleh et al. (Biomarker Insights; 2018;13:1-10. DOI:10.1177/1177271918771969) teach that Galectin-3 KO mice showed reduced myocardial macrophage infiltration after acute MI and that Galectin-3 levels were higher in patients with early systolic dysfunction, and predicted 3-month major adverse cardiovascular event (see abstract).
Hemadou et al. (J. Am. Heart Assco. 2021; 10:e016287. DOI:10.1161/JAHA.120.016287) teach that P3 scFv-Fc-2c specifically targeted atherosclerotic plaques in the Apoe−/− mouse model (see abstract).
Fontayne et al. (US11091552, issued Aug 17, 2021, priority Oct 5, 2018) teach a method of treating atherosclerosis by administering to a subject in need thereof an anti-Gal3 antibody at multiple doses including 0.05mg comprising a VH having the sequence of SEQ ID NO:1 and a VL having the sequence of SEQ ID NO:2 (col. 13-14, claims 1-17).
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Chang-Yu Wang
January 14, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675