Detailed Specification
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 following:
Group I, an ABPC and pharmaceutical composition comprising the same (i.e., claims 1-13, 15-21, 24, and 41),
Species A, parent CD22 antibody inotuzumab,
Species B, species of inotuzumab, MYT4424 (i.e., Seq ID Nos: 127 and 2)
in the reply filed on 11 April 2022 is acknowledged.
Status of the Claims
Claims 1-45 were originally filed 3 January 2022 and the preliminary amendment filed 1 June 2022 has been entered.
Claims 42-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group (i.e., methods), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11 April 2025.
Claims 1-4, 8-13, 15-18, 20, 21, 24, 41, and newly added claims 46-48 are under consideration.
Priority
The instant application claims priority to PCT/US2020/041268 filed 8 July 2020 and to U.S. provisional applications i. 62/932,864 (referred to herein as ‘864 application) filed 8 November 2019, ii. 62/902,220 (referred to herein as ‘220 application) filed 18 September 2019, and iii. 62/871,466 (referred to here as ‘466 application) filed 8 July 2019.
Newly amended claims are drawn combinations of histidine substitutions in parental anti-CD22 ABPC comprising i. Seq ID Nos: 1 and 2 (i.e., inotuzumab), ii. Seq ID Nos: 143 and 144 (i.e., pinatuzumab), iii. Seq ID Nos: 268 and 269 (i.e., TRPH-222), iv. Seq ID Nos: 366 and 367 (i.e., ADCT-602), v. Seq ID Nos: 410 and 411 (i.e., 12C5), and Seq ID Nos: 489 and 490 (i.e., 19A3) (see specification para spanning pgs. 2-3).
The provisional ‘864 application is directed to pharmaceutical compositions and methods comprising an effective amount of a CD22 ABPC specifically histidine or alanine substitutions of the heavy chain of pinatuzumab (see ‘864 application claim 2, Seq ID Nos: 13-103).
The provisional ‘220 application is directed to pharmaceutical compositions and methods comprising an effective amount of a CD22 ABPC specifically histidine or alanine substitutions in inotuzumab (see ‘220 application claim 2, Seq ID Nos: 13-52).
The provisional ‘466 application is directed to pharmaceutical compositions and methods comprising an effective amount of a CD22 ABPC specifically histidine substitutions of the heavy chain of inotuzumab (see ‘466 application claim 2, Seq ID Nos: 13-51).
The above provisional applications do not recite or contemplate CD22 antibodies TRPH-222, ADCT-602, 12C5, or 19A3 (e.g., see claims 1c (i.e., TRPH-222), 1e (i.e., 12C5), 1f (i.e., 19A3)).
Therefore, the priority date for the instant claims 1-4, 8-13, 15-18, 20, 21, 24, and 41 is that of PCT/ US2020/041268 filed 8 July 2020.
Withdrawn Claim Objections
In view of Applicant amending claim 11 the claim objection is hereby withdrawn.
Withdrawn Rejections
In view of Applicant amending claim 8 to remove the clauses associated with the indefiniteness, and amending claim 9 to depend from claim 4 the 35 USC 112(b) rejections are hereby withdrawn.
In view of Applicant amending claim 8 to limit the pairs of VH and VL sequences to those engineered from a single parent CD22 antibody and cancelling claims 5-7 the 35 USC 112(d) rejection of claims 5-8 is hereby withdrawn.
In view of Applicant amending claims 1, 4, 21, and 24 to incorporate particular pairs of VH and VL sequences all prior art rejections under 35 USC 102 and 35 USC 103 are hereby withdrawn.
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 1-4, 8-13, 15-18, 20, 21, 24, 41, and 46-48 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 CD22 antibodies with particular VH and VL sequences (i.e., CDRs with specific substitutions or specific combinations of substitutions), does not reasonably provide enablement for the following:
Particular pairs of a CD22 ABPC or CD22 epitope binding ABPC with the functional properties recited in claims 1, 2, 4, 8-11, 21, and 24.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 Fed 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the breadth of the claims, the amount of direction or guidance provided, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
A. The Breadth of the Claims
Claims 1, 4, 8, 16, 18, 21, 24, and 46-48 are drawn to an ABPC or a pharmaceutical composition comprising an ABPC that specifically binds CD22 or a CD22 epitope wherein the ABPC comprises particular VH and VL pairs and either has a faster dissociation rate or greater dissociation constant (KD) at a pH of about 4-6.5 than at a pH of about 7-8. Therefore the language of claims 1, 4, 8, 16, 18, 21, 24, and 46-48 encompass a genus of structures with the claimed dissociation rate or KD property over the claimed pH range (i.e., pH 3.75-6.74 and 6.75-8.5).
Claims 2, 4, 9, 10, 11, and 24 are drawn to additional functional properties of the APBC to include i. degradation of the ABPC following internalization by the target mammalian cell (claims 2 and 24), ii. increased toxin liberation, cell killing, or endolysosomal delivery in the target mammalian cell as compared to a control (claims 4, 9 in part, 10 in part), iii. less of a reduction or no detectable reduction in the level of CD22 on the surface of the target mammalian cell (claim 11), or iv. decreased in vivo half-life compared to a control ABPC (claim 19). It is noted claims 4, 9, 10, 11, and 24 are drawn to comparison with “a control ABPC” defined in the specification as capable of binding CD22 or an epitope of CD22 on the surface and either a dissociation rate or a KD between 0.1-3 fold faster or greater at a pH of about 4-6.5 than a pH of about 7-8 (see specification pg. 22, 1st full para). Alternatively, the “control ABPC” can be the parental antibody (no substitutions) of those disclosed in the working examples (e.g., inotuzumab) (see specification pg. 22, 1st full para, end). The language of claims 2, 4, 9, 10, 11, and 24 encompass a genus of antibodies to include antibody fragments (e.g., VHH) which bind to any CD22 epitope (e.g., conformational, linear, non-linear) with the claimed dissociation rate or KD property and one or more additional functional property as compared to any CD22 ABPC with the recited function.
Claims 8 and 46-48 are drawn to antibodies comprising a more limited list of particular VH or VL sequences (claim 8). The language of claims 5-8 encompasses genera of antibody fragments comprising a minimal structure of i. a VH/VL alone (e.g., VH or VHH domain) or paired with an undefined partner (claims 5 and 8), ii. HCDRs1-3/LCDRs1-3 alone or paired with undefined corresponding CDRs (claim 6), or iii. a VH or VL with a single histidine substitution variable CDRs (i.e., 90% sequence identity) (claim 7).
and E. The State of the Art and The Level of Predictability in the Art
Regarding independent claims 1, 4, 21 and 24 (i.e., a faster or greater dissociation rate or constant, respectively at pH 4-6.5 compared to 7-8), the state of the art teaches histidine scanning approaches for engineering pH sensitive antigen binding domains are reliable; however, developing pH sensitive antibodies has several challenges and a high level of unpredictability regarding the particular position(s) or combination of positions with histidine substitutions result in a pH sensitive antibodies.
Murtaugh teaches, “the library-based histidine scanning approach is both general and robust, and is capable of producing numerous highly pH sensitive antibody variants that would not be generated
using traditional design methods” (see Murtaugh et al. A Combinatorial Histidine Scanning Library Approach to Engineer Highly pH-Dependent Protein Switches. Protein Science, 2011, 20: 1619-1631).
In addition, using a combinatorial library wherein all the VHH interface positions sample histidine Murtaugh engineered several pH dependent anti-RNase A antibodies, identifying both “hot” (e.g., HCDR1 position 27, 29, and 33) and “cold” (e.g., HCDR1 positions 34 and 35) positions for histidine substitutions (see Murtaugh figure 2A). Bovin and colleagues isolated pH dependent CXCL10 antibodies de novo from phage display antibodies libraries enriched in histidine content (see Bovin et al. (2015) De novo isolation of antibodies with pH-dependent binding properties. mAbs 7:2, pgs. 294-302, in particular sentence spanning pgs. 295-296, Table 1). Different groups have successfully engineered pH sensitive antibodies (e.g., IL-6R, PCSK9) using histidine scanning in the CDRs and framework positions important for antigen binding (see Igawa et al. (2010) Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nature Biotechnology Vol. 28, No. 11, referred to herein as Igawa2, pg. 1203, 2nd col. last para, figure 1, Table 1; see Riggers et al. (2012) Increasing Serum Half-life and Extending Cholesterol Lowering in Vivo by Engineering Antibody with pH-sensitive Binding to PCSK9. Journal of Biological Chemistry, Vol. 287, Iss: 14, pgs. 11090-11097, pg. 11091, 1st col. 2nd para, pg. 11092 para spanning cols 1-2). However, in both cases histidine scanning was done across all residues and only a subset of residues were identified as conferring pH sensitivity (see Igawa pg. 1203, 2nd col. last para , 1st sent; see Riggers pg. 11092, 1st col. last para). Igawa2 discloses pH dependent tocilizumab variants with histidine substitutions in HCDR1 positions 27, 31, and 35 and LCDR1 positions 28, 32, and LCDR2 position 55 while Riggers discloses a pH sensitive pCSK9 antibody with substitutions at HCDR2 position 52, LCDR position 30, and LCDR2 position 50 (see Igawa pg. 1204, 1st col.; see Riggers pg. 11092 para spanning cols 1-2).
Furthermore, Murtaugh teaches, “In practice, engineering pH-sensitive binding through the introduction of one, two, or more ionizable groups into a protein interface is a difficult task as simple correlations between a histidine’s pKa and its structural environment are not obvious. This is a problem that cannot be solved through prediction or simulation as we cannot predict shifts in pKa with sufficient accuracy. Furthermore, the inserted ionizable residue must not only undergo a pKa perturbation on binding but also not dramatically interfere with high-affinity binding at the permissive pH. Previous approaches to insert histidine residues within a protein interface were often guided by structural knowledge of the protein complex; however, such approaches have limitations as only a small subset of the structural and energetic space is ultimately sampled. These techniques also tend to be time and cost intensive. Finally, although knowledge of the protein complex structure may certainly be useful toward engineering pH sensitivity, many, if not most, antibody affinity reagents are limited to knowledge of only the amino acid sequence” (see Murtaugh, in particular pg. 1621, 1st col. last para).
In addition, “Although a wild-type to histidine substitution inserts a protonation site, it is not necessarily sufficient to introduce pH dependence as the histidine must exhibit a pKa change on forming the protein– protein complex. There is no single structural ‘recipe’ for such a change in proton affinity” (see Murtaugh pg. 1627, 1st col. 1st full para).
Applicant echoes these teachings, disclosing a histidine substitution in the antigen binding domain can either weaken or enhance the binding affinity (see specification pg. 318, 4th para).
Regarding claims 1-4, 8-13, 15-18, 20, 21, 24, 41, and 46-48 (i.e., claims encompassing variable CDRs), the state of the art teaches CDR sequences are the residues required for antigen binding and these sequences are highly variable in order to facilitate binding to a multitude of antigens (see Kapingidza et al. 2020. Antigen-Antibody Complexes. Vertebrate and Invertebrate Respiratory Proteins, Lipoproteins and other Body Fluid, CH 19, pgs. 465-484, pg. 468, lines 1-4). Culang also teaches that CDRs are widely assumed to be responsible for antigen recognition (see Culang et al. The structural basis of antibody-antigen recognition. Front. In Immun. 2013. Vol. 4, Article 302, pgs. 1-13, abstract). The mutation effects at interfaces are often unpredictable and more often than not result in decreased binding affinity (see Clark et al. Influence of canonical structure determining residues on antibody affinity and stability. Journal of Structural Biology 185 (2014) 223–227, pg. 223, 2nd col. 1st full para). For example, pairing substitutions LCDR1 (i.e., M32L) in the AQC2 antibody with the conservative substitution Y70F retained nearly wildtype affinity while pairing with V29I lost nearly all binding affinity (see Clark, Table 1, pg. 223, 2nd col. 1st full para). In addition, a M32I substitution parried with a A25F substitution resulted in no binding (see Clark, Table 1, pg. 223, 2nd col. 1st full para). Similarly, Brown demonstrates only 1 of 15 T15 antiphosphocholine Abs with single substitutions loss antigen binding while 16 of 31 antibodies with 2-4 mutations loss antigen binding (see Brown et al. Tolerance to Single, but Not Multiple, Amino Acid Replacements in Antibody VH, CDR2. J Immunol (1996) 156 (9): 3285–3291, pg. 3285, 1st col. 1st para, Table 1, pg. 3290 1st col. last para). Therefore, a person of ordinary skill in the art would understand that as little as two substitutions in the CDR regions of an antibody can result in a complete loss of binding for the target.
Based on the unpredictability of the art and the breadth of the claims, the instant specification must provide a sufficient and enabling disclosure commensurate in scope with the instant claims.
F. and G. Amount of Direction Provided by the Inventor/Existence of Working Examples
Applicant has made a series of CD22 antibodies using six parental (i.e., no-substitutions) CD22 antibodies as “a control ABPC”. Using inotuzumab as an example, Applicant made antibodies comprising a histidine substitution or alanine where a histidine was already present in every position of HCDRs1-3 and LCDRs 1-3 of inotuzumab (see specification pg. 318, 4th para, pg. 319, 1st para, sentence spanning pgs. 337-338, pg. 339 middle, pg. 342 last para, pg. 344 starting on line 11, MYT0519-0557 (HCDRs 1-3), MYT1642-1673 (LCDRs 1-3)), Drawings pg. 729-730, figures 43 and 44). Applicant discloses a subset of these single mutants were either i. selected for further analysis, ii. lost CD22 binding, or iii. maintained CD22 binding and had a less than 1-fold change in KD or dissociation rate (see specification para spanning pgs. 338-339, pg. 340, end of 1st para, pg. 343 bottom 1/3 of the page, pg. 345, 1st para). Constructs selected for further analysis exhibited either i. enhance dissociation at pH 5.4, ii. reduced dissociation at pH 7.4, or iii. both (see specification para spanning pgs. 338-339, pg. 340, end of 1st para). Applicant systematically combined two or more substitutions from those variants identified in the single mutant scan of either the heavy chain (HC) or light chain (LC) (see specification pg. 341, starting in line 4, pg. 345 last sentence, MYT1621-1640 (HC), pg. 334 starting in line 11, pg. 347 middle, MYT4436-4439(LC)). Similar to the single substitution variants a subset from each chain were selected for further analysis (see specification pg. 341, last sentence through pg. 342, pg. 345, 1st para, sentence spanning pgs. 346-347, pg. 348 end of 1st para). The combination HC and LC variants were subsequently combined with each other wherein Applicants selected a subset for further analysis using the same criteria (see specification pg. 348, last para, pg. 349 end of 1st para).
It is noted examples 9 and 12 or 10 and 13 are the same experiment with different CD22 antigens. Applicant discloses the ABPC showed higher affinity for the Sino Biological antigen at pH 5.4 compared to the Acro Biosystems antigen and the Sino Biological antigen was more correlated with increases in endolysosomal delivery (see specification pg. 341, 1st para). Therefore, Applicant discloses the antibodies within the scope of the instant claims (e.g., claims 1 and 21) depends not only the particular ABPC but also the particular CD22 antigen selected. For example, using the Acro Biosystems antigen the histidine substitutions in MYT0525 and MYT0528 obliterated CD22 binding (i.e., not within the scope of claims 1 and 21) (see specification pg. 338, bottom) while these same ABPC using the Sino Biological antigen, not only exhibited CD22 binding, but were also selected for further analysis for exhibiting either i. enhance dissociation at pH 5.4, ii. reduced dissociation at pH 7.4, or iii. both (i.e., within the scope of claim 1 and 21) (see specification pg. 343 bottom 1/3). Furthermore, using the Acro Biosystems antigen, MYT0545 was selected for its enhanced functional properties (i.e., within the scope of claims 1 and 21) (see specification pg. 338 bottom) while CD22 binding was obliterated using the Sino Biological antigen (i.e., outside the scope of claims 1 and 21) (see specification, pg. 343 bottom 1/3). Applicant also demonstrates combining histidine substitutions from single variants with enhanced functional properties did not necessarily result in either enhance dissociation at pH 5.4 or reduced dissociation at pH 7.4. For example, MYT4419 did not exhibit any of the desired functional properties despite comprising enhanced single substitution variants MYT0524 (i.e., position 31 of Seq ID No: 1 or 6 of Seq ID No: 3), MYT0531 (i.e., position 52 of Seq ID No: 1, or position 3 of Seq ID No: 4), and MYT0550 (i.e., position 103 of Seq ID No: 1, or position 7 of Seq ID No: 5) each of which were selected for further analysis based on enhanced functional properties using both CD22 antigens (see Seq ID No: 122, specification sentence spanning pgs. 346-347, pg. 447, drawings pgs. 103, 110, 114, and 209, Figures 8g, 8n, 8r, and 12am). Even ABPCs comprising sub-combinations of MYT4419 were identified as having enhanced functional properties. For example, MYT4401 (i.e., positions 31 and 52), MYT4405 (i.e., positions 31 and 103), MYT4409 (i.e., positions 52 and 103) (see specification pgs. 443-445, Seq ID No: 104, 108, and 112, Drawings pg. 191, 195, and 199, Figure 12u, y, and ac). Thus, Applicants demonstrates a high level of unpredictability as to which positions or combination of positions will result in the claimed functional properties for a given CD22 antibody. Regarding increased endolysosomal deliver in a target mammalian cell, Applicant disclose only a subset of antibodies with either enhance dissociation at pH 5.4 and/or reduced dissociation at pH 7.4 also have this property (see specification pg. 371, last full sentence of example 30, Figure 60a-d, drawings pgs. 746-749). Using pinatuzumab and a variant thereof Applicant demonstrates increased dissociation at a lower pH leads to enhanced internalization and endolysosomal delivery in target mammalian cells (see specification pg. 372, bottom, figure 61a-d).
H. The Quantity of Experimentation Needed to Make the Invention
Applicant discloses pH engineered ABPC specific for CD22 can be generated either by using published CD22 antibodies and introducing mutations or de novo identification of CD22 ABPC using naïve libraries or libraries with defined CDR compositions and screening under appropriate conditions (see specification pg. 318, 3rd para). Histidine scanning can be used to identify pH sensitive antibodies due to histidine’s ability to turn positively charged at or below pH 6; however, Applicant notes that this can both weaken or enhance the binding affinity of the interaction (see specification pg. 318, 4th para). Whether histidine weakens or enhanced the binding affinity is determined by not only the ABPC but also the corresponding charge of and interactions with the antigen epitope (see specification pg. 318, 4th para). Furthermore, the functional properties in claims 4, 9-11, and 24 are in comparison to a “control ABPC” which includes any CD22 antibody with a 3-fold or less change in either the dissociated rate or KD at about pH 4.0-6.5 compared to about pH 7.0-8.0.
Conclusion
Considering the absence of a structure function correlation for determining the particular residues which result in the instantly claimed antibody functions and the high level of unpredictability as to which positions or combination of positions in a given CD22 antibody will result in the desired pH dependent property across the range of pH claimed as taught by both Applicant and the state of the art the entire scope of experimentation required to identify ABPC encompassed by the breadth of the structures (e.g., VHH, 90% sequence identity) and functions (e.g., dissociation rate or constant, increased toxin liberation, mammalian cell killing, decreased half-life) of ABPCs that bind CD22 or an epitope of CD22 is left to those skilled in the art. The present claims and disclosure amount to an invitation to the skilled artisan to develop such embodiments. Given the resource intensive nature of the required experimentation, i.e., de novo antibody discovery or histidine scanning each individual CD22 antigen binding domain in the context of a particular antigen and particular control ABPC, the skilled artisan would reasonably conclude that such experimentation would be unnecessarily, and improperly, extensive and undue.
Applicant's arguments filed 24 December 2026 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant amended the claims to specify particular pairs of VH and VL sequences and pointed to redacted versions of Figures 43-46 for support for the claimed functional properties (see Remarks pg. 22 last para, Figure 43 (see Remarks pg. 23), Figure 44 (see Remarks pgs. 23-24), Figure 45 (see Remarks pgs. 24-26), and Figure 46 (see Remarks pg. 46, middle)). It is noted Figures 48 (see Remarks pg. 27), 49 (see Remarks pgs. 27-28), 50 (see Remarks pg. 28), 52 (see Remarks pg. 29), 53 (see Remarks pgs. 29-30), 54 (see Remarks pg. 30), 55 (see Remarks pg. 31), 56 (see Remarks pgs. 31-32), 57 (see Remarks pg. 32), 58 (see Remarks pg. 33), and 59 (see Remarks pg. 33) are drawn to non-elected parent antibodies subject to a Markush rejection (see below).
Applicant is claiming antibodies with particular combinations of VH and VL sequences with pH dependent functional properties (e.g., Seq ID Nos: 14 and 2; see claim 1(a), second para and claim 1(i) or (ii)). The data Applicant has pointed to for support for possessing one of the two claimed functional properties is the raw data from biolayer interferometry using a single pH value within the claimed range (i.e., 5.4 or 7.4) that can be used to calculate the claimed functions. Evidence of pH sensitivity is not sufficient to enable the claim because the language of the claim requires particular antibody characteristics (i.e., dissociation rate or constant) to have a particular change (i.e., faster or greater) when transitioning from a neutral pH to an acidic pH. The dissociation rate measures how fast a complex breaks apart at a specific moment and depends on concentration (i.e., koff x [ligand]) while the dissociation constant is a fixed value indicating the probability of dissociation that is independent of concentration (i.e., kon/koff). An antibody can have substantially different kinetics at different pHs and yet the same overall KD. In addition, the y-axis across the breadth of instantly claimed structures is not consistent nor is there any indication of statistical significance for the findings. For example, the instant claims are drawn to an antibody comprising Seq ID Nos: 14 and 2 (see below left panel) represented in Figure 2c and an antibody comprising Seq ID Nos: 19 and 2 (see Remarks Figure 43 pg. 23, 1st line and 4th line) represented in Figure 2h (see below right panel).
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*black box to highlight the difference in data representation
First, it is unclear which functional property MYTO0525 possesses, i.e., if the dissociation rate is faster at the acidic pH as compared to the neutral pH, or alternatively is the dissociation constant (KD) is greater at the acidic pH as compared to the neutral pH from the data presented in the right panel. The traces appear largely overlapping. Furthermore, it unclear if MYT0525 (right panel) were displayed using the same y axis as MYT0520 (left panel) the claimed changes in these properties would be discernable for MYTO0525. Other claimed examples (but not limited to) where it is unclear what particular property is pH sensitive include MTY0528, MYT0532, MTY1647 (see Figures 2k, 2o, 4f; see below in order).
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Arrows indicate the same value on the y axis. Even if Examiner were to concede these antibodies exhibited one of the two claimed functional properties, given the largely overlapping values or similar binding curves it is unclear if the claimed function remains inherent across the broad range of pHs currently claimed.
Therefore, the 35 USC 112(a) rejection (i.e., enablement) for instant claims 1-4, 813, 15-18, 20, 21, 24, 41, and 46-48 is hereby maintained.
Claims 1-4, 813, 15-18, 20, 21, 24, 41, and 46-48 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the 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. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
Generic claims drawn to substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with a particular functional property or properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding, binding to a certain epitope), claiming antibodies solely with reference to said functional property, e.g., claiming the genus of all ABPC that bind CD22 or an epitope of CD22 that have either a faster or greater dissociation rate or KD, respectively at a pH of 4-5 compared to a pH of 7-8.0, would not be sufficient to meet the written description requirement when the structures of antibodies having those properties have not been adequately described. See Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
In particular MPEP § 2163 instructs that the “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice…reduction to drawings…or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus…See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").”
The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by functional characteristic, such as its ability to bind tnfr1, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995).
As stated above claims 1, 4, 8, 16, 18, 21 and 24 are drawn to a genus of ABPCs defined by particular combinations of VH and VL sequences and a single functional property. Claims 2, 4, 9-11, and 24 are drawn to either one or more additional functional properties while claims 8 and 46-48 are drawn to further limiting the structure of the ABPC (e.g., a subset of particular VH and VL pairs) (see above).
Applicants have shown histidine scanning for CDR residues of 6 known CD22 antibodies; however, disclose no evidence for the inherency of the instantly claimed property over the breadth of the instantly claimed pH ranges.
The specification teaches histidine substitution into the CDR regions of an antigen binding domain can either weaken or enhance binding affinity while the state of the art teaches,
“simple correlations between a histidine’s pKa and its structural environment are not obvious. This is a problem that cannot be solved through prediction or simulation as we cannot predict shifts in pKa with sufficient accuracy” (see specification pg. 318, 4th para; see Murtaugh pg. 1621, 1st col. last para).
It is evident from the inotuzumab variants that the claimed functional properties result from a combination of the particular ABPC and the CD22 antigen chosen (see specification pg. 342, 1st full para; see above). It is also evident the claimed ABPC functions are a result of particular histidine substitutions or combinations of substitutions with no structure function correlation; thus, the particular substitutions and combinations thereof cannot be used to inform the substitutions necessary for the claimed functions in alternative CD22 antibodies (see above for summary of Applicant’s examples).
Each of the 6 known CD22 antibodies comprises unique VH, VL, and CDR sequences. There is no evidence from the disclosure that antibodies with the claimed VH and VL pairs exhibit the claimed functional property over the instantly claimed pH ranges.
A person of ordinary skill in the art at the time of filling would understand pH sensitive antibodies have kinetic properties which change as the pH changes. Overall, based on the disclosure, the state of the art at the time of filing, a skilled artesian would have recognized that the applicant was not in possession of the claimed invention at the time of filing.
Applicant's arguments filed 24 December 2026 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant argues the claim has been amended to recite the pairs of VH and VL sequences with the claimed functional properties (see Remarks pg. 34, 2nd para).
As state above Applicant has pointed to particular sets of VH and VL pairs and their respective raw data from biolayer interferometry experiments using a single pH value in the claimed acidic range and a single pH value in the claimed neutral pH range. However, it was known in the art at the time of filing that pH can abolish binding of a pH sensitive antibody (see Bogen et al. (2019). Dual function pH responsive bispecific antibodies for tumor targeting and antigen depletion in plasma. Front. Immunolo. Vol. 10, Art. 1892, pgs. 1-13, in particular Figure 3B, pg. 5, 2nd col. 3rd para). Bogen also discloses pH sensitive variants have increased dissociation rates orders of magnitude different as pH becomes more acidic. For example, CEACAM6 pH sensitive variant CV2 had a koff of 11.5 at pH 7.4, a koff of 55.5 at pH 6.0, a koff of 167 at pH 5.5, and a koff of 450 at pH 5.0 (see Bogen Table 1). Following this trend the ordinary artisan would understand at the pH shifted higher, or closer to neutral (e.g., pH approaches 6.5) the value of koff is going to approach the value of koff in the claimed neutral pH range. Given the degree of changes the ordinary artisan would recognize many of the antibodies instantly claimed would not exhibit the instantly claimed properties as inherent over the breadth of the instantly claimed pH range. Applicant has not demonstrated the instantly claimed antibodies bind across the breadth of the instantly claimed acidic pH. For example, even if the Examiner were to concede MYT1647 (see below) exhibited one of the claimed properties at a pH 5.4 compared to a pH 7.4, the teachings from the state of the art suggests this claimed difference may not be present at a less acidic pH.
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Therefore, the 35 USC 112(a) rejection (i.e., written description) for instant claims 1-4, 813, 15-18, 20, 21, 24, 41, and 46-48 is hereby maintained.
Claim Rejections - 35 USC § 112(b)
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.
Claim 4, 9-11, 24, 46 and 48 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 4, 9-11, 21, and 24 are drawn to functional properties compared to “a control ABPC”. As stated above the specification defines “a control ABPC” as capable of binding CD22 or an epitope of CD22 on the surface and either a dissociation rate or a KD between 0.1-3 fold faster or greater at a pH of about 4-6.5 than a pH of about 7-8 or the parental antibody (no substitutions) of those disclosed in the working examples (e.g., inotuzumab) (see specification pg. 22, 1st full para, end). Claims 1, 21, and 24 are drawn to ABPC with a faster or greater (e.g., 1 fold) dissociation rate or KD, respectively. It is unclear how the “control ABPC” can be both the measure by which ABPC are determined as within the scope (i.e., faster or greater than the “control APBC”) implying the control ABPC is not within the scope of claims yet the definition of “a control ABPC” with a dissociation rate or a KD between 0.1-3 fold faster or greater at a pH of about 4-6.5 than a pH of about 7-8 is within the scope of claims.
Applicant's arguments filed 24 December 2026 (referred to herein as Remarks) have been fully considered but they are not persuasive.
Applicant argues the specification teaches the “control ABPC” can be pinatuzumab, inotuzumab, ADCT-602, TRPH-222, 12C5, and 19A3 (see Remarks pg. 35, 1st para). While the specification discloses these structures are within the scope of the “control ABPC” the definition is not limited to these structures.
Therefore, the 35 USC 112(b) rejection of claims 4, 9-11, 24, 46 and 48 is hereby maintained.
The following objections/rejections are necessitated by amendment.
Claim Rejections - 35 USC § 112(d)
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.
Claims 1-4, 9-13, 15-18, 20, 21, 24, and 41 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnish, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parted Ohsumi, 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 § 2117.
The Markush grouping of claims 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: Claims 1-4, 9-13, 15-18, 20, 21, 24, and 41 (i.e., in particular claims 1, 4, 21, and 24) are drawn to various CD22 antigen binding domains comprising pairs of VH and VL sequences with engineered substitutions across 6 distinct parent antibodies (i.e., inotuzumab (e.g., claim 1(a)), pinatuzumab (e.g., claim 1(b)), TRPH-222 (e.g., claim 1(c)), ADCT-602 (e.g., claim 1(d)), 12C5 (e.g., claim 1(f)), and 19A3 (e.g., claim 1(g)) each with unique CDR sequences (i.e., unique structure) (see specification starting in the middle of pg. 3-pg. 4, 1st para). Therefore, claims 1, 4, 21, and 24 are drawn to antibodies that do not share substantial structural features (i.e., CDRs). Furthermore, each parent antibody has unique functional properties (e.g., binding affinity, constant regions, CD22 epitope) and subsequent variants for each parent have additional unique functional properties (i.e. the dissociation or dissociation constant). Therefore, given the unique functions for each parent CD22 antibody, claims 1, 4, 21, and 24 do not share a common use.
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.
Allowable Subject Matter
The following inotuzumab sequence variants are free and clear of the prior art:
Wherein the heavy chain variable domain is selected from the group consisting of Seq ID No: 32, 36, and 127; and the light chain variable domain comprises Seq ID No: 2.
The above is derived from Applicant’s currently claimed Seq ID Nos.
Conclusion
No claim allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/H.A.P./ Examiner, Art Unit 1644
/AMY E JUEDES/ Primary Examiner, Art Unit 1644