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 .
Election/Restrictions
Applicant’s election without traverse of the Group comprising claim 59 in the reply filed on 6/15/2025 is acknowledged. The restriction requirement is made final.
Applicant is correct in their response that the subject matter of Groups II, claim 58, and Group III, claim 59, were reversed. Elected claim 59 is, as pointed out by Applicant, a method of treating or alleviating a symptom of… an autoimmune disease. All pending claims are drawn to this method.
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The claimed invention is drawn to a method of treating an autoimmune disease or disorder and not the fusion proteins themselves.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, 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.
Claim Rejections - 35 USC § 112(a)
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 59-82 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.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The claims are drawn to a method of treating, alleviating symptoms of, ameliorating and/or delaying the progression of an autoimmune disease or disorder, comprising administering a therapeutically effective amount of an isolated polypeptide that binds at least DR5 and comprises a plurality of DR5BDs, wherein each DR5BD is a VHH, each VHH comprises CDR1-3 of SEQ ID NO:128, 131 and 130, respectively, and wherein adjacent DR5BDs are operably linked by an amino acid linker. The important aspect of the claim is set forth in the preamble, that is, the polypeptide must be able to treat, alleviate symptoms of, ameliorate and/or delay the progression of an autoimmune disease or disorder. To that end, the enablement issues deal with two aspects of the polypeptide that appear to be central for activity: the necessary presence of an IgG Fc region able to bind FcγR, and the sequence of the framework regions (FRs) between the CDRs. Enablement is also an issue for the method of treating, etc., an autoimmune disease or disorder. It is noted independent claim 59 recites no function (e.g., agonistic or antagonistic/blocking) associated with the isolated polypeptide aside from binding “at least DR5”.
Assuming the method is enabled, which it is not agreed that it is and will be discussed further below, the polypeptide used in the method must itself be enabled. The structure of the polypeptide determines its function aside from binding DR5, e.g., whether it activates or blocks DR5 signaling. The disclosed polypeptides used in the working examples are all agonistic multivalent constructs comprising particular VHH antibodies. The polypeptides of instant claims 63-66, 72-74 and 82 are defined by full VHH sequences and would reasonably be expected to be agonistic. That is not the case for those polypeptides defined only by CDR1-3 as discussed later. Further, it appears any polypeptide used in the instant experiments comprises at least two DR5BDs and two IgG Fc regions, with each Fc linked to at least one DR5BD, forming a bivalent or higher order construct ([0087]). Examples of structures of the polypeptide of the claimed invention are presented in Figure 1, all of which comprise an Fc region comprising a CH2 and CH3 domain to which at least one VHH is fused, wherein fusion is through an IgG hinge region when the VHHs are fused to the CH2 domain. The necessity of the presence of an IgG Fc region is suggested in the specification in [0084], in which it is discussed that dimerization of two cell surface DR5 receptors is not sufficient to activate the cell death pathway. In vitro typical immunoglobulin antibodies specific for DR5 require a crosslinking agent in order to induce DR5 activity because the clustering of only two DR5 receptors is not sufficient for activity. However, when the bivalent DR5 antibodies were administered in mouse models of human cancers, the antibodies showed significant activity. “This activity was later shown to be dependent on mouse FcgammaR (FcγR) receptors. Clinical studies in humans failed to reproduce the robust responses seen in these pre-clinical mouse models. The lack of activity in humans is hypothesized to be due to insufficient antibody crosslinking.” The prior art also supports the need for an Fc receptor-binding region for anti-DR5 antibodies for anti-tumor activity, including through immune cell activity. For example, Takeda et al. (J. Exp. Med. 199(4):437-488, 2004, cite in the IDS filed 4/4/24) summarized their findings using anti-mouse DR5 monoclonal antibody (mAb) in an immunocompetent mouse syngeneic tumor model by saying (p. 438, col. 2, end of first paragraph), “This mAb not only inhibited the growth of TRAIL-sensitive tumor cells in vivo without toxicity, but also primed tumor-specific T cells that could eradicate TRAIL-resistant variants. The critical contribution of FcR-bearing innate immune cells to these processes was revealed.” In vitro it was found that the antibody was highly cytotoxic against 4T1 cells when crosslinked by FcR on P815 cells, but activity was abolished by anti-FcR mAb (Fig. 1C). The same inhibition of cytotoxic activity was found when the antibody was in the presence of 4T1 cells and macrophages or NK cells and anti-FcR mAb (Fig. 2A). “The fact that macrophages and NK cells effectively mediated MD5-1 cytotoxicity via their FcR implied a possible cytotoxic effect of MD5-1 in vivo.” In FcγR-/- mice lacking FcγRI and FcγRIII, there was no mAb antitumor effect, even though there was in TRAIL-/- and FcγRIIB-/- mice (Figs. 4E-4F). From the data, it was concluded that “[A]ctive induction of DR5-mediated tumor cell apoptosis in concert with the recruitment of FcR-expressing innate immune cells was required for optimal induction of tumor-specific CTLs [cytotoxic T lymphocytes].” (p. 445, col. 2, middle of first paragraph). In agreement with this FcR-induced immune cell activity, van der Horst (Blood Adv. 5(8):2165-2172, 2021, cite in the IDS filed 4/4/24) reviewed the HexaBody-DR5/DR5 antibody in preclinical trials. This antibody is formed of two different non-competing DR5 IgG1 antibodies, each with a mutation in the Fc domain that facilitates hexamer formation between the IgG antibodies by enhancing Fc-Fc interactions between antibodies (Visual Abstract and second sentence of Abstract). The formation of DR5 antibody hexamers allows the antibodies to activate the DR5 death pathway to induce apoptosis independent of FcγR-mediated antibody crosslinking (p. 2166 col. 1, second paragraph). However, the activity was significantly reduced when hexamers were not formed, i.e., in the constructs without the hexamerization-enhancing mutated Fc domain (Fig. 1A). It is stated (p. 2167, col. 2, first paragraph), “The cytotoxic activity of IgG1-DR5/DR5 may be attributable, at least in part, to the presence of FcγR+ cells (eg, NK cells) in the BM [bone marrow] suspensions that can induce FcγR-dependent ADCC and/or crosslinking of membrane-bound antibodies.” This means that whether the Fc domain facilitates hexamer formation of the antigen-binding regions attached thereto or crosslinking and FcγR-dependent ADCC, an Fc region is necessary for agonistic DR5 antibody activity. This reasonably appears to be the case for the instant DR5BD-containing polypeptide of the instant methods, particularly for induction of apoptosis (Figs. 3A -C). As described in the post-filing Inhibrx website (https://inhibrx.com/inbrx-109/#scroll, 2023, cite in the IDS filed 4/4/24), the Inbrx-109 tetravalent VHH DR5 agonist has an Fc domain with a disabled effector function. There are two points to make for the INBRX-109 molecule. First, it has an Fc domain, which is what appears to provide the proper structure/placement for the VHH single domain antibodies so they can bind and multimerize DR5 receptors on a cell. Second, there is no apparent means for the INBRX-109 to activate DR5 other than through the Fc domain. Like the HexaBody-DR5/DR5 discussed above, the predominant antitumor activity of INBRX-109 is due to activation of the extrinsic apoptotic pathway. This is consistent with the instant specification that notes in [0085], “Importantly, the fusion proteins of the present disclosure are capable of eliciting apoptosis of DR5 expressing cells independently of exogenous crosslinking agents.” This does not exclude the activation of immune cells through FcR binding of the polypeptide’s Fc domain. To this end, the skilled artisan would have reasonably expected that an IgG Fc domain is required to maintain the necessary conformation of the DR5BDs of the instant polypeptide used in the claimed method to multimerize DR5 receptors on a cell leading to activation of the extrinsic apoptotic pathway, even if the Fc effector function was disabled. If the Fc was able to bind its receptor(s), one skilled in the art would also reasonably expect it to engage FcγR to enhance tumor cell destruction through activation of immune cells, e.g., NK cells; however, it is unclear how this relates to treatment of an autoimmune disease.
In addition to the Fc region being part of the polypeptide of the claims, the structure of the DR5-binding portion is important. It is not only the CDRs that are involved in antigen binding, but also framework regions (FRs) that flank the CDRs. The FR amino acids affect function of the antibody in terms of specificity and affinity for the antigen. The unpredictability of amino acid sequences for FRs which can function in the context of a VHH is supported by Noёl et al. (Biochimie, 131:11-19, 2016, cited in the IDS filed 4/4/2024), which showed that FRs of VHH, once considered ‘constant’ in terms of sequence and structure as opposed to the variable CDR regions, are themselves variable (p. 13, col. 2, start of third paragraph). It is shown that the ability to predict the FRs on the basis of other known FRs is low (paragraph bridging pp. 14-15). They found that amino acids in an FR can affect the conformation of different FRs in a VHH (e.g., p. 17, col. 2, second paragraph). As summarized in the ABSTRACT, “This work is the first study to analyse the structural diversity of FRs of VHHs. Using a structural alphabet that allows approximating the local conformation, we show that each of the four FRs do not have a unique structure but exhibit many structural variant patterns. Moreover, no direct simple link between the local conformational change and amino acid composition can be detected. These results indicate that long-range interactions affect the local conformation of FRs and impact the building of structural models.” This shows the complexity of FRs and their interactions with each other and with CDRs in VHH. Saerens et al. (J. Mol. Biol. 352:597-607, 2005, cited in the IDS filed 4/4/2024) demonstrated that even a single amino acid difference in framework can abolish binding activity (see page 599, column 2, final paragraph). This is relevant because in determining appropriate treatment one must know whether the therapeutic agent is an agonist or antagonist. The search by Saerens et al. for a universal VHH framework scaffold and studies on CDR grafting between two highly homologous VHHs led to the realization (p. 600, paragraph bridging cols. 1-2), “These data demonstrate the feasibility to exchange CDR-Hs of various length and structure between two VHHs with a high degree of identity in their frameworks. However, they also illustrate how the nature of particular amino acids at key positions within the scaffold might seriously limit the success rate of transferring the antigen specificity by exchange of loops even among homologous frameworks.” Further, for the single universal framework chosen by Saerens et al., all chimeras chosen belonged to the same VHH subfamily (#2) and a different framework was incapable of being used as a scaffold (p. 603, col. 1, third paragraph, and col. 2, third paragraph). One universal-type VHH framework scaffold and the highly related framework sequences of the instantly disclosed 1F5 VHH antibodies of the instant specification does not support the breadth of VHH constructs encompassed in the claims which are silent with respect to FRs surrounding the recited CDR1-3. A therapeutic method requires not mere binding of the target, but also requires at least one particular activity, e.g., being a DR5 agonist, and must have the specificity (i.e., not to bind related receptors such as DR4 or decoy receptors), with sufficient affinity and avidity to be of therapeutic benefit.
For an antibody-based therapeutic to be useful it must be both safe and effective. However, the specification discusses ([0012]) the dangers of administering single domain antibodies recognized by HAVH (anti-VH) autoantibodies in humans, which target an epitope within human VH domains. “Thus, it expected that humanized camelid-derived VHHs would also be recognized by HAVH autoantibodies as the target epitope seems to be cryptic and located within human germline framework regions. The interaction of HAVH autoantibodies (also called anti-drug antibodies (ADA) or anti-single domain antibodies (ASDA), herein) can cause enhanced clustering and activation.” The case of single domain antibody (sdAb) TAS266 inducing hepatotoxicity during Phase I clinical trials is noted as being mostly due to interaction of HAVH autoantibodies (a.k.a. anti-drug antibodies, ADA). Working Example 3 of the specification showed (Fig. 7A) that TAS266 antibody was bound by HAVH, however, instant antibody Tet-hz1F5v5 was not. Further, as shown in Figs. 8A-9D, antibody TAS266 showed autoantibody recognition-dependent hepatotoxicity, while instant hzVHH-Fc polypeptides did not unless a secondary antibody provided crosslinking. The hepatotoxicity of TAS266 was reduced when the sdAbs were modified at amino acid position Leu11 and at the C-terminal region of each of the sdAbs (corresponding to the first and fourth FRs, [0073]). This supports the criticality of the FR of sdAb as responsible for HAVH binding. For therapeutic utility, binding of an antibody by HAVH greatly diminishes any benefit the antibody might provide.
While there is in vitro and preclinical evidence using various mouse models of autoimmune disease or disorder (for autoimmune thyroiditis, multiple sclerosis (MS or EAE), autoimmune arthritis, rheumatoid arthritis (RA), diabetes and colitis) showing that manipulation of DR5 activity can reduce the severity of certain conditions, the extent of its involvement or generalized activity over the vast variety of autoimmune diseases or disorders is unknown and the modulation is different depending on the diseases/condition. It is important to note two things about the autoimmune data related to DR5. First, many of the experiments focus on TRAIL, the ligand for not only DR5, but also DR4, decoy receptors DcR1 and DcR2 and soluble receptor osteoprotegrin (OPG; Martinez-Lostao et al., Biochemical Pharmacology 83 (2012) 1475–1483, at p. 1476, first paragraph). Second mice do not have DR4, the only other receptor besides DR5 that can elicit a proapoptotic signal (Martinez-Lostao et al., ibid.), As discussed by Martinez-Lostao et al. (p. 1479, col. 1, second paragraph) it has been shown that in a mouse MS model, inhibiting TRAIL led to inflammation in the central nervous system and worsening of symptoms, which was also confirmed using a TRAIL-deficient mouse. But in a mouse model of human MS called EAE (Experimental Autoimmune Encephalomyelitis), blocking TRAIL activity significantly reduced the severity of disease, with the conclusion that, “Therefore, Apo2L/TRAIL may have a dual role in MS, controlling self-reactive immune cells in the periphery and contributing to neural damage in the inflamed CNS.” Human synovial cells from RA patients were sensitive to TRAIL-induced apoptosis and in the mouse model TRAIL blockade exacerbates autoimmune arthritis (collagen-induced arthritis; Martinez-Lostao et al., supra, p. 1479, col.1, paragraphs 3 and 4,). However, in the experiments of Audo et al. (Cytokine, 64:81-90, 2013, p. 15, col.1, third paragraph) with fibroblast-like synoviocytes (FLS) from RA patients it was found ex vivo sensitivity to TRAIL-induced apoptosis varies to such an extent that it was concluded in patients with TRAIL-sensitive FLS, TRAIL decreases synovial hyperplasia, while FLS from patients with more severe RA are resistant to TRAIL-induced apoptosis but responsive to TRAIL-induced proliferation, thereby supporting synovial hyperplasia. “Thus, the simple use of TRAIL to treat synovial hyperplasia is not feasible…” Looking at a different disease model, both TRAIL and an agonistic DR5 monoclonal antibody reduced severity of experimental autoimmune thyroiditis (EAT, Martinez-Lostao et al., supra, paragraph bridging pp. 1479-1480). However, DR5 is expressed by both normal and infiltrating lymphocytes in thyroiditis tissue, and TRAIL is expressed in normal and thyroiditis-derived glands, though few lymphocytes express TRAIL (Bretz et al., Cell Death Diff. 9:274-286, 2002, at p. 281, col. 1). Bretz et al. discuss autoimmune thyroiditis and that it appears to be accompanied by an increase in cell surface expression of DR5. Activation of DR5 by TRAIL leads to apoptosis of thyroid cells and DR5 antibodies also cause apoptosis of thyroid cells (ibid.) that would lead to destruction/damage of the thyroid, which is not a desirable treatment outcome. The general lack of applicability of DR5-directed therapeutics to autoimmune disease and disorders is summarized in the post-filing reference of Alves et al., (The FEBS J. 288(19):5530-5554, 2020):
The initial observation that TRAIL preferentially triggers apoptosis of cancer cells led to a great number of studies, which sought to dissect the mechanisms involved in the sensitivity and resistance to apoptosis of cancer cells and healthy cells, respectively. In spite of substantial advance in the field, TRAIL signaling revealed to be much more complex than first thought, and a fair number of questions are still unsolved. The lack of knowledge on the precise molecular events triggered by TRAIL signaling in different cells and conditions is a major drawback to fully understand the physiological roles of the TRAIL pathway. This is due to the biological difficulties in dissecting the cell-specific variations, the impossibility to avoid the crosstalk between pathways and the influence of the external stimuli to the cells. Another important unknown aspect is how the different pathways triggered upon TRAIL-R activation are regulated intracellularly…. Additional post-translational regulations, such as glycosylation, or selective engagement of any of the four TRAIL receptor or the ligand itself may also be at work to dictate which signaling pathway will be activated [[247]]. The TRAIL system gathers the most complex set of receptors among TNF members, yet most studies fail to explore, in an exhaustive manner, the role of each of these receptors, often focusing on either TRAIL-R1 or TRAIL-R2. Clearly, a better understanding of the molecular events involved in regulating apoptotic and nonapoptotic TRAIL signaling is needed, not only to understand TRAIL biology but also to envision the development of successful therapies relying on TRAIL or its derivatives.
Because of the pleiotropic effects of TRAIL and apparently DR5, the teaching in the prior and post-filing art about the complexity and unpredictability of treating autoimmune diseases with a polypeptide that either activates or inhibits DR5 (noting that the polypeptides of the instant working examples are agonistic), the lack of working examples of treating any autoimmune disease or model thereof, and the lack of guidance or direction for said treatment in terms of which autoimmune conditions could be treated with an agonist versus an antagonist with a reasonable expectation of success, in addition to the lack of activity of the claimed polypeptide beyond binding DR5, it would require undue experimentation to practice the method of the invention commensurate in scope with the claims. Additionally, for the reasons discussed above, which include the breadth of the claims in terms of lack of designated FRs and/or lack of IgG Fc domain, the support in the prior art and specification for importance of the role of the Fc domain maintaining a bivalent or higher order VHH structure for DR5 and activation as well as for the particularity of FRs, the unpredictability and complexity of which amino acids in FRs can be substituted with a reasonable expectation of success, and the lack of guidance, direction or working examples concerning alternative FRs beyond the 1F5 variants for a VHH having the CDRs of claim 59, it would require undue experimentation to practice the method of the invention commensurate in scope with the claims.
Prior Art
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure.
Aktas et al. (Neuron, 46:421-432, May 2005) showed that in a mouse model of multiple sclerosis (T cell-induced experimental autoimmune encephalomyelitis, EAE), intracerebral delivery of TRAIL increased clinical deficits, while delivery of soluble DR5:Fc reduced neuronal damage (p. 425). It is concluded that “TRAIL contributes to neural damage in the inflamed brain.” (end of Summary)
WO 2011/098520 A1 (cited in the IDS filed 4/4/2024) is cited in the instant specification for teaching the tetravalent VHH DR5 agonist polypeptide TAS266 (e.g., [0068]). This polypeptide is used as a control in several of the working examples.
US 9,120,855 (cited in the IDS filed 4/4/2024) teaches DR5 single domain antibodies. These antibodies do not have the same CDR sequences as the instant invention and the patent does not teach or suggest the instant invention.
Conclusion
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Claire Kaufman
/CLAIRE KAUFMAN/
Primary Examiner, Art Unit 1674
August 1, 2025