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 .
Status of Claims
Claims 22-43 are currently pending.
WITHDRAWN OBEJCTIONS and/or REJECTIONS
Applicant’s arguments, see Remarks filed November 4, 2025, with respect to:
Objection to the specification,
Objection to claim 24, and
Rejection of claims 28 under 35 U.S.C. § 112(b)
have been fully considered and are persuasive. The aforementioned grounds of objection and rejection have been withdrawn.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Objections
37 C.F.R. 1.71(a) requires the claims to be written in “full, clear, concise, and exact terms[.]” Claims 22 stands and claim 38 is objected to because of the following informalities:
Claim 22 in lines 3 recites “light chain variable segment (VL) segments”, which should be “light chain variable (VL) segments[.]” Similarly line 5 recites “light chain joining segment (JL) segments”, which should be “light chain joining (JL) segments[.]” Additionally, “VL” should be “VL” in line 4.
In claim 38 parts a) and b) an IgL/IgH locus “comprising human sequence” is not grammatically correct. Suggested languages is “comprising a human sequence.”
Applicant's arguments filed 4, 2025 have been fully considered but they are not persuasive. Applicant argues that the claims are amended as requested (pg. 7 in the first ¶). However, claim 22 has not been amended as requested. Where VL is indicated in claim 22 as standing in for “light chain variable segment”, each recitation of “VL segment” (e.g. claim 24) would be read as “light chain variable segment segment.”
Claim Rejections - 35 USC § 112
Claim 38 stands rejected and claims 32 and 43 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second ¶, 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.
Applicant's arguments filed November 4, 2025 have been fully considered but they are not persuasive.
Applicant argues that the amendment obviates the rejection over claim 38 (pg. 7 in the second ¶). However, claim 38 remains indefinite because the skilled artisan would not be reasonably appraised of the scope of an IgL/IgH locus “comprising human sequence.” For example, how many amino acids from a human sequence would need to be part of the IgL/IgH locus for one of skill to determine that the IgL/IgH locus “comprises human sequence”? Some skilled artisan would interpret claim 38 as comprising, e.g., replacing at least 2 amino acids with at least 2 amino acids that have been obtained from a human sequence. Other skilled artisans would argue that to be able to determine whether infringement occurs, the human sequence has to have a number of amino acids sufficient to demonstrate that a portion of the IgL/IgH locus is human by using alignment tools known in the art.
To advance prosecution claim 38 parts a) and b) are interpreted as comprising at least one feature (e.g. recombination signal sequence, CTCF binding element, V segment, D segment, J segment, etc.) wherein said feature has the sequence of a human feature.
Claims 32 and 43 recite “a CTCF-binding element (CBE) within the nucleic acid separating the 3’ end of an exogenous heavy chain variable (VH) segment.” The metes and bounds of the limitation are indefinite because it is unclear from what the CBE separates the 3’ end of the exogenous VH segment. Does the scope include a CBE element separating the 3’ end of the exogenous VH segment from the 3’ end of the first native VH segment that is 3’ of the exogenous sequence? Does the scope include a CBE element separating the 3’ end of the exogenous VH segment from the 5’-most DH segment?
To advance prosecution on the merits, the aforementioned limitation recited in claims 32 and 43 is interpreted with the scope of an IgH locus comprising an exogenous VH segment 5’ of an adjoining CBE.
Claim Rejections - 35 USC § 103
Claims 22-26, 28-36, 38-39, and 42 stand rejected under 35 U.S.C. 103 as being unpatentable over MacDonald et al. in US 10,980,221 B2 published April 20, 2021 in view of Liu et al. April 2006. Immunity. 24:405-415, cited herewith; evidenced by Proudhon et al. Adv Immunol. 2015 Aug 20. 128:123-182.
Applicant's arguments filed November 4, 2025 have been fully considered but they are not persuasive.
Applicant argues unexpected results (see pg. 7 in the penultimate ¶ through pg. 13). Examiner holds that the allegations of unexpected results are not persuasive in view of the expected results of 2-fold increase in LC-CDR3 diversity from the teachings of MacDonald and insufficiencies in establishing that the claimed subject matter results in the observed trends in LC CDR3 diversity by Luo.
The instant specification teaches two factors that affect CDR3 diversity: 1) different combinations of V and J segments and 2) non-templated de novo mechanisms such as N region additions by TdT (¶ [00268] on pg. 103). The teachings of MacDonald and Luo, insofar as they have been discussed in relation to the allegations of unexpected results, are further expounded upon below.
Teachings of MacDonald1
The Velocimmune model used by MacDonald has at least 20 Vk segments (see Fig. 8 and col. 3, line 64 through col. 4, line 3) and 5 Jk segments (see Fig. 9 and col. 4 in lines 4-9). The number of possible combinations of Vk and Jk segments for the Velocimmune model is 20 x 5 = 100.
MacDonald’s Dual Chain model has two Vk segments - IGKV3-20 and IGKV1-39 - and 5 Jk segments – IGKJ1, IGKJ2, IGKJ3, IGKJ4, and IGKJ5 (Fig. 16 and col. 4 in lines 46-51). Thus, the diversity of CDR3s is restricted in the Dual Chain model by limited options for Vk-Jk combination (10 possible Vk-Jk combinations).
Figure 13 as shown below has been annotated to more transparently show the estimated number of unique LCDR3 per 10,000.
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612
884
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Greyscale
% of unique LC CDR3s when TdT is present (experimental)
% of unique LC CDR3s when TdT is not present (control)
Factor by which TdT increases % of unique LC CDR3s over control (experimental divided by control)
MacDonald Fig. 13 Velocimmune
~18%
~8%
~18/~8 = ~2.25
MacDonald Fig. 13 Dual Chain
~8%
~3%
~8/~3 = ~2.67
Note well, MacDonald shows that, regardless of the model used, adding TdT results in approximately a 2-fold increase in LC-CDR3 diversity. Therefore, the skilled artisan would expect that the combination of MacDonald’s Velocimmune model comprising TdT and Liu’s nonfunctional mutation in Cer/Sis would result in a 2-fold increase over an appropriate control system lacking TdT. Applicant notes that considering diversity as measured by unique CDR3s per 10,000 CDR3s controls for the differences in sources of data between Luo (i.e. instant inventors’ work) and MacDonald and the change in the total number of antibody formation events due to recombination (pg. 10 in the last ¶ spanning pg. 11). However, comparing the data while taking into the appropriate controls is a better way to systematically evaluate the differences between the prior art and the instant invention.
Analysis of Luo’s data and comparison to MacDonald’s2
The VH1-2RJH2/Vk3-20R model of Luo has the following features:
VH1-2RJH2 (see second col. on pg. 2 in the first full ¶):
The most D-proximal mouse VH segment is replaced with human VH1-2
Inactivated IGCR1 element
All mouse D segments are retained
Mouse JH segments (interpreted as all JH segments) are replaced with human JH2 (interpreted as a single JH2 segment)
Vk3-20R (see pg. 4 in the first col. at the top of page):
Replaced the mouse proximal Vk3-7 with human Vk3-20
Intact Cer/Sis element
The skilled artisan would reasonably assume that all remaining mouse Vk + the single human Vk and all mouse Jk segments contributed to CDR3 diversity, which in a C57BL/6 mouse is 101 Vk segments and 4 Jk segments3 (101 x 4 = 404 possible combinations).
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760
780
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Greyscale
% of unique LC CDR3s when TdT is present (experimental)
% of unique LC CDR3s when TdT is not present (control)
Factor by which TdT increases % of unique LC CDR3s over control (experimental divided by control)
MacDonald Fig. 13 Velocimmune
~18%
~8%
~18/~8 = ~2.25
MacDonald Fig. 13 Dual Chain
~8%
~3%
~8/~3 = ~2.67
Luo Fig. 1D VH1-2RJH2/Vk3-20R
~40%
~18%
~40/~8 = ~2.22
On pg. 11 of Remarks in the last ¶ Applicant maintains the position that Fig. 1D of Luo 2023 represents the scope of claim 22 and demonstrates superior diversity over what one would have expected from MacDonald in view of Liu.
However, arguments directed to unexpected properties “must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). ‘A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.’ In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original).” (MPEP716.02(e)).
As discussed supra, Fig. 1D represents diversity of LCDRs CDR3s in a model having an intact Cer/Sis element, whereas the claimed subject matter requires that the IgL locus has a nonfunction Cer/Sis element. The increased diversity of LC CDR3s could be explained by the fact that the VH1-2RJH2/Vk3-20R model of Luo has 4 times as many possible Vk-Jk arrangement as the Velocimmune model of MacDonald. Moreover, the addition of TdT consistently shows approximately a 2-fold increase in LC CDR3 diversity over control. Thus, when all other factors are accounted for by analyzing the data in comparison to a proper control, the degree to which the LC CDR3 diversity increases as shown in Luo Fig. 1D is entirely expected from MacDonald in view of Liu.
Discussion on Fig. S6B of Luo4
The features of the VH1-2RJH2/Vk1-33RCSΔ model (pg. 2 in the last ¶ spanning pg. 3) are similar to the VH1-2RJH2/Vk3-20R model, except the light chain has a) the mouse Vk3-2 segment replaced with human Vk1-33, leaving all remaining mouse Vk and Jk segments intact, and b) a non-functional Cer/Sis element. While all murine Vk and Jk segments were available for recombination, measurement of CDR3 diversity was only observed from Vk1-33-rearranged segments (4 possible Vk-Jk combinations).
The labels for the y-axis on Fig. S6B are askew, however the person of ordinary skill would have reasonably assumed that the top mark from which all the graph’s lines starts is 100%. The annotations below show where a skilled artisan would have reasonably extrapolated each trend to reach 10,000 total LC CDR3s. Thus, the TdT enhanced model would have been interpreted as roughly half-way between 0 and 25% of unique LC CDR3s at 10,000 total LC CDR3s. This analysis yields a slightly different interpretation than Applicant’s.5
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834
942
media_image3.png
Greyscale
% of unique LC CDR3s when TdT is present (experimental)
% of unique LC CDR3s when TdT is not present (control)
Factor by which TdT increases % of unique LC CDR3s over control (experimental divided by control)
MacDonald Fig. 13 Velocimmune
~18%
~8%
~18/~8 = ~2.25
MacDonald Fig. 13 Dual Chain
~8%
~3%
~8/~3 = ~2.67
Luo Fig. 1D VH1-2RJH2/Vk3-20R
~40%
~18%
~40/~8 = ~2.22
Luo Fig. S6B VH1-2RJH2/Vk1-33RCSΔ
~12%
~6%
~12/~6 = ~2
“Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).” (MPEP 716.02; emphasis added).
“The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.")” (MPEP 716.02(b)).
As one of skill would have expected, the addition of TdT to the Cer/Sis deleted model of Luo produced a roughly 2-fold increase in LC CDR3 diversity. Therefore, there is no synergistic effect of combining exogenous TdT with a nonfunctional Cer/Sis. The question of whether the instantly claimed invention produces unexpectedly high LC CDR3 diversity hinges on whether the absolute magnitude of Lou’s Vk1-33 CDR3 diversity is higher than MacDonald’s reported dual chain LC CDR3 diversity to such an extent that the difference is really unexpected. The magnitude of both Luo’s VH1-2RJH2/Vk1-33RCSΔ with TdT and the control are elevated over the corresponding experimental and control groups of MacDonald’s Dual Chain model; is this observed phenomenon caused by Cer/Sis deletion or, given that “[a]ny differences between the claimed invention and the prior art may be expected to result in some differences in properties” In re Merck & Co Id., is the phenomenon resultant from differences between the biological systems and methods of evaluation used by MacDonald and Luo? Under the standard of “preponderance of the evidence,” there is insufficient evidence to conclude that the allegations of unexpectedly high properties are attributable to the effect of Cer/Sis deletion on LC CDR3 diversity.
There are differences in experimental methods and condition used by MacDonald and Luo that more likely than not contribute to differences in observations.
MacDonald’s measured from total splenic CD19+ B-cells (see col. 106 in lines 53-56 and col. 110 in lines 46-49), while Luo measured from naïve B cells (see Fig. S6 caption).
MacDonald extracted CDR3 sequences using IMGT boundaries to define CDR3 sequences from sequences obtained by RACE PCR (Example 2, col. 106 spanning col. 107). Luo generated HTGTS-Rep-seq libraries by using bait primers targeting Jk1, Jk2, Jk4, and Jk5 from DNA and annotated CDRs with IgBLAST (pg. 9 in the second para of the second col.). RACE PCR uses cDNA, which is obtained from mRNA. Thus, MacDonalds measured the diversity of transcribed CDR3 sequences, whereas Luo conducted observations from untranscribed DNA. Each B cell will express multiple mRNA copies of the same gene, therefore the results reported in MacDonalds is skewed toward a lower apparent diversity by virtue of the fact there is an increased representation of the same sequences.
Luo obtained splenic naïve B cells for sequences from young (5 to 8 week old) mice (pg. 9 in the last ¶ of the first col. spanning the second col.). While MacDonald does not disclose the age of mice used in experiments, young mice have a higher antibody diversity in spleen samples than older mice.6
There is no evidence that Cer/Sis deletion accounts for the observed increase in Vk1-33 LC CDR3 diversity over the prior art.
While it was known at the time of instant filing that disruption of the Cer/Sis element increases utilization of J-proximal V segments7, there is no evidence in the art that Cer/Sis deletion increases LC CDR3 diversity for a given Vk segment. The teachings of the instant specification regarding junctional diversification are related to N region additions by TdT and the combination of different Vk segments with different Jk segments. 8 There is no explicit or implicit direction in the instant specification or evidence from the working examples that a nonfunctional Cer/Sis element will result in increased CDR3 diversity for a given Vk segment. Nor is there any direction or evidence that combining a nonfunctional Cer/Sis with TdT results in a synergistic or additive effect on CDR3 diversity for a given Vk segment. The only experimental evidence relating to the IgL locus in the instant specification shows that Cer/Sis deletion increases utilization of J proximal Vk segments (see Fig. 15), which was already known in the prior art,4 and humans have more non-template additions at the Vk-Jk junction than mice (Fig. 20). In fact, the instant specification discloses that it is addition of TdT expression that permits increased antibody diversification resulting in a more human-like Igk repertoire (see, e.g. ¶ [101] on pg. 33). As discussed above, the effect of additional TdT expression, i.e. 2-fold increase in CDR diversity, is an expected property that would have been apparent to the skilled artisan from the teachings of MacDonald.
In summary, the allegations of unexpectedly high properties are not persuasive because the degree to which adding TdT enhances LC CDR3 diversity was expected from the prior art. "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). Additionally, in view of the differences in methods used by MacDonald and Luo, there is insufficient evidence that the magnitude of LC CDR3 diversity increase can be attributed to the claimed subject matter. Therefore, Applicant has not met the burden for establishing that the results of Luo are unexpected and significant. See MPEP 716.02(b).
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. § 716.01(d).
Claims 22-26, 27, 28-36, 37, 38-39, 40, 41 and 42 stand and claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over MacDonald et al. in US 10,980,221 B2 published April 20, 2021 in view of Liu et al. April 2006. Immunity. 24:405-415, cited herewith; evidenced by Proudhon et al. Adv Immunol. 2015 Aug 20. 128:123-182 as applied to claims 22-26, 28-36, 38-39, and 42 above, and further in view of Alt et al. WO 2015112790 A2 published July 30, 2015.
Claim 43 is rejected on the same grounds set forth in the Office Action mailed August 6, 2025. MacDonald’s VELOCIMMUNE heavy chain loci necessarily comprises a CBE 3’ of an exogenous VH. “Regarding instant claims 22 b), 28, and 32 a), though MacDonald does not expressly teach a CBE between an exogenous VL/H segment and the first VL/H that is 3’ of said exogenous VL/H segment, CBEs known to exist between VL/H segments (see Proudhon on pg. 9 in the first full ¶ and Figures 2-3 on pgs. 32-35). Therefore, the VELOCIMMUNE® human variable light and heavy chain loci as taught by MacDonald have a CBE between exogenous human VL/H segments and the first segment which is 3’ of said exogenous human segment, there being no evidence to the contrary.” (OA pg. 7 in the first full ¶).
“Alt teaches that modifying the IGCR1 sequence to be non-functional results in a larger proportion of antibodies utilizing the 3’ most VH segment.” (OA pg. 10 in the first full ¶).
It would have been prima facie obvious to combine MacDonald in view of Liu with the teachings of Alt for the same reasons stated on pg. 11 of the OA in the last ¶ spanning pg. 12.
Applicant's arguments filed November 4, 2025 have been fully considered but they are not persuasive.
Insofar as Applicant has not pointed out any deficiencies in the prima facie case other than those pertaining to the combination of MacDonald and Liu, the instant claims, by a preponderance of evidence, remain unpatentable for all the same reasons set forth supra.
Conclusion
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/B.K.S./Examiner, Art Unit 1644
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683
1 As compared to Applicant’s analysis on pgs. 8 through 10.
2 As compared to Applicant’s on pg. 11 in the last ¶ and table at the bottom of the page.
3 Aoki-Ota et al. J Immunol. 2012. 188(5):2305-2315.
4 As compared to Applicant’s analysis on pgs. 12 through 13.
5 Applicant interprets the TdT enhanced model as have a frequency of ~20% unique LC CDR3s (see Remarks on pg. 12) which is more than the estimated 12% produced by the present analysis.
6 Ma et al. Immunity & Ageing. 2021. 18:17, cited herewith; see Fig. 6B on pg. 9.
7 Xiang et al. J Immunol. 2011 May 1. 186(9):5356-5366; see pg. 7 in the second full ¶ through 8 in the first full ¶
8 Specification in ¶ [00268] on pg. 103; ¶ [00275] through [00276] on pg. 105; [00298] on pg. 114.