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 .
DETAILED ACTION
Application status
In response to the previous Office action, a non-Final rejection (mailed on 02/19/2026), Applicants filed a response and amendment received on 06/19/2026. Said amendment canceled Claims 3, 6, 11, 13-14, 17, 20, 23-35 and 37-88, amended Claims 1, 5 and 21, and added Claims 89-92. Thus, Claims 1-2, 4-5, 7-10, 12, 15-16, 18-19, 21-22 and 89-92 are at issue and present for examination.
It is noted by the Examiner that Claim 36 is withdrawn from further consideration by the Examiner, 37 CFR 1.142(b) as being drawn to a non-elected invention in the previous Office actions, a non-Final rejection (mailed on 02/19/2026).
Claim Rejections - 35 USC § 112 – WITHDRAWN
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The previous rejection of Claim 5 for the recitation of "recombinant human serum albumin" in claim 1, is withdrawn by virtue of Applicants’ amendment.
Claim Rejections - 35 USC § 102 – WITHDRAWN
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The previous rejection of Claims 1-2, 4, 7, 16, 18-19, 21, 25-26 and 29 under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Mehtala et al. (Cys34-PEGylated Human Serum Albumin for Drug Binding and Delivery, Bioconjug Chem. 2015 May 20; 26(5): 941–949, see IDS), is withdrawn by virtue of Applicants’ amendment.
Claim Rejections - 35 USC § 103 – MAINTAINED as necessitated by Applicants’ amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 4-5, 7-10, 12, 15-16, 18-19, 21-22 and 89-92 are rejected under 35 U.S.C. 103 as being unpatentable over Mehtala et al. (Cys34-PEGylated Human Serum Albumin for Drug Binding and Delivery, Bioconjug Chem. 2015 May 20; 26(5): 941–949, see IDS) in view of Kim et al. (US Patent No. 9775914), Bradbury et al. (US Patent No. 10548989), an evidentiary reference of Buckel et al. (Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery, Cancer Res. 2015 April 1; 75(7): 1376–1387), and KSR International Co. v. Teleflex Inc., 550 U.S.--, 82 USPQ2d 1385 (2007).
The instant claims are drawn to a composition comprising an albumin drug conjugate wherein the albumin is recombinant human albumin, wherein the drug and recombinant human albumin are conjugated ex vivo, wherein the drug is monomethyl auristatin E (MMAE).
Mehtala et al. teach a composition comprising an albumin drug conjugate wherein the albumin is recombinant human albumin, wherein the drug is paclitaxel, which belongs to the class of chemotherapeutic drugs known as taxanes, and wherein the recombinant human albumin is covalently conjugated ex vivo at Cys-34 via a maleimide linker comprising 5- or 20-kDa mPEG spacer (see abstract, “MATERIAL AND METHODS” ON pages 7-10, Scheme 1 on page 23. Mehtala et al. further teach that the albumin and drug-linker conjugate are conjugated at a molar ratio of 1:5 (see Figure 9 (b)). Mehtala et al. further teach that [1] recombinant human albumin is at a concentration of 25 mg/mL (see page 3 under “Synthesis and Characterization of PEGylated HAS adducts”); and [2] drug to albumin ratio is 10:1 (see Table 1 on page 24).
Mehtala et al. do not teach MMAE as a drug, a cathepsin-B sensitive valine-citrulline dipeptide linker, recombinant human albumin concentrations of 5 mg/mL to 15 mg/mL, and drug to albumin ratios of 1:1 to 3:1.
Kim et al. teach a chemotherapeutic prodrug conjugate comprising: an albumin-binding moiety such as maleimide, which is joined through a caspase 3-cleavable peptide linker, which is conjugated to a chemotherapeutic agent monomethyl auristatin E (boldfaced for added emphasis), wherein the cleavable linker is positioned between the MMAE and the albumin (see claims 1-3 and 8-11 of ‘914 patent).
Bradbury et al. teach a cathepsin-B cleavable valine-citrulline dipeptide linker (see column 19, lines 13-15).
It would have been obvious to a person of ordinary skill in the art (POSITA) prior to the effective filing date of the instant application to make and use the composition comprising an albumin drug conjugate as taught by Mehtala et al. and replace the drug from paclitaxel to another chemotherapeutic drug MMAE while using many cleavable linkers taught by Kim et al. and Bradbury et al. A POSITA would have been motivated to make and use such composition because [1] MMAE is much more potent than paclitaxel as a chemotherapeutic drug as evidenced by Buckel et al. (see the direct comparison of IC50 between MMAE and paclitaxel in Figure 1D, and also abstract); and [2] cleavable linkers provide site-specific payload release within tumor cells, thereby reducing toxic effects on normal cells that are neighboring cancer cells.
Claims 5, 22, 89 and 90 are included in this rejection in accordance with MPEP 2144.05 “Optimization & Result Effective Variables”. It discusses that result-effective variables can be optimized, especially when a particular parameter is recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation. In the instant case, Mehtala et al. teach that [1] recombinant human albumin is at a concentration of 25 mg/mL (see page 3 under “Synthesis and Characterization of PEGylated HAS adducts”); and [2] drug to albumin ratio is 5:1 or 10:1 (see Figure 9 (b); and Table 1 on page 24), which can be optimized for different chemotherapeutic drugs with different potencies, which is the case between MMAE and paclitaxel. Therefore, the use of human albumin is at a concentration of 5 mg/mL to 15 mg/mL as well as the use of the molar ratio of drug to albumin is 1:1 to 3:1 would have been obvious to one of ordinary skill in the art as being result effective variables, and would be characterized as routine experimentation.
A POSITA would have had a reasonable expectation of success to make and use such composition because all of the required biochemical reagents and techniques were readily available and rampantly used as evidenced by Mehtala et al., Kim et al. and Bradbury et al. prior to the filing of the instant application.
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Applicants’ Arguments:
The Action relies on Kim as the source of MMAE as a drug payload. However, Kim's entire system is built upon a fundamentally different principle of operation from that claimed. Maleimide is a functional group that binds endogenous albumin and prolongs the plasma circulation of the prodrug conjugates. After intravenous administration, the prodrug covalently binds to the circulating albumin and accumulates in tumor tissue. The maleimide-MMAE conjugate of Kim is specifically designed to bind circulating endogenous albumin in vivo after intravenous administration; not to be pre-formed with recombinant albumin ex vivo before administration.
The claimed invention, by contrast, requires that the drug and recombinant human albumin be conjugated ex vivo, prior to administration. Adopting the ex vivo conjugation approach of Mehtala would require discarding the in vivo albumin-binding mechanism that is the very foundation of Kim's prodrug design. As the MPEP makes clear, if a proposed modification would render the prior art being modified unsatisfactory for its intended purpose, there may be no suggestion or motivation to make the proposed modification. MPEP § 2143.01. The intended purpose of Kim's maleimide-MMAE conjugate is spontaneous in vivo binding to circulating endogenous albumin. Substituting ex vivo conjugation to recombinant albumin would eliminate this in vivo binding mechanism entirely, rendering the Kim system inoperable for its intended purpose.
Moreover, Applicant respectfully submits that the specification of the instant application contains precisely evidence, in the form of direct head-to-head comparative pharmacokinetic and efficacy data comparing the claimed ex vivo recombinant albumin-MMAE conjugate (ALDC1) against the in vivo albumin-binding prodrug (MMAE-MAL) that is the closest analog taught by Kim. These results are unexpected and are not predicted by the combined teachings of the cited references. The specification at paragraph [00102] discloses that the pharmacokinetic profiles of free MMAE and total MMAE in plasma were measured by LC-MS in MIA PaCa2 xenografts, with equivalent amounts of MMAE from various treatment arms administered at a single dose to each group of mice (0.5 mg/kg), and total MMAE in plasma, comprising both released MMAE and conjugated MMAE, was measured by LC-MS.
The results of this direct comparison are striking. The AUC (area under the curve, i.e., total drug exposure in plasma over time) of total MMAE in the ALDC1 group was significantly higher, which was 160% of that in the MMAE-MAL group and 200% of the ALDC3 group. This finding is attributable to premature cleavage and rapid clearance of MMAE in the MMAE-MAL and ALDC3 groups, where in both arms MMAE was more susceptible to being cleaved and prematurely released in plasma, resulting in faster clearance than the ALDC1 group.
This 60% improvement in total drug exposure over the in vivo albumin-binding prodrug of Kim, and a 100% improvement over the higher-DAR conjugate, represents a difference in magnitude that a person of ordinary skill in the art would not have predicted from the combined teachings of the cited references. The Action's proposed combination, i.e., substituting MMAE for paclitaxel in Mehtala's ex vivo PEGylation platform, provides no basis for predicting this pharmacokinetic advantage. As to the DAR, the specification discloses a critical and unexpected structural finding: the conformational structure of albumin-drug conjugates was characterized by circular dichroism (CD) spectroscopy. Minima ellipticity peaks were observed at 208 and 222 nm. The spectra of ALDC1 aligns with the spectra of native albumin, indicating that the secondary structure of albumin has not been altered after conjugation of a single payload to Cys34. However, the secondary structure of ALDC3 showed a different CD spectrum in comparison to albumin and ALDC1.
This finding is mechanistically explained by the nature of the conjugation sites involved. Controlled reduction was used to expose a limited number of thiols from the total 17 disulfide bonds present in albumin. Most of the disulfide bonds were located in the a-helix region of albumin. Though the reaction was controlled, the number and location of exposed free thiols were heterogenous, as supported by the LC-MS spectra of ALDC3. Partial reduction and subsequent addition of multiple drugs to albumin may impact the structure of albumin, which has been reflected in changes to the secondary structure of ALDC3.
Neither Mehtala nor Kim discloses or predicts this structural consequence of increasing the drug-to-albumin ratio. Mehtala works exclusively with PEG chains conjugated at Cys-34, i.e., a non-cleavable, non-therapeutic modification, and circular dichroism analysis of the PEG-(C34)HSA derivatives indicated negligible changes in secondary protein structure relative to n- HSA. S-PEGylation at Cys-34 has minimal influence on the secondary structure of HSA. Mehtala's finding of structural preservation at Cys-34 with PEG chains does not predict what occurs when multiple drug-linker conjugates are loaded onto albumin by partial reduction of disulfide bonds, which is a fundamentally different conjugation chemistry that disrupts the a- helix region. The Action's assumption that the drug-to-albumin ratio is simply a parameter to be optimized ignores this critical structural distinction. Site-specific loading of drug to albumin at 1:1 ratio allowed the conjugate to maintain the native structure of albumin and its intrinsic properties. This preservation of native structure is not a predictable outcome of varying the drug-to-albumin ratio, rather it is an unexpected consequence of the specific combination of site-specific conjugation at Cys-34 and a 1:1 loading ratio that avoids the disulfide bond disruption required to achieve higher DARs.
The structural preservation of albumin at the 1:1 ratio translates directly into unexpected functional advantages in drug release. The specification discloses that when incubated without Cathepsin B, the released MMAE from ALDC1 and ALDC3 was not detectable during the investigated period, indicating that the albumin-drug conjugates were stable without Cathepsin B. Upon incubation with Cathepsin B, ALDC1 and ALDC3 released 94.73% and 90.62% of the conjugated MMAE within 40 min, respectively. However, the kinetics of release differ in a manner that reflects the structural heterogeneity of ALDC3.
This heterogeneity in ALDC3 is a direct consequence of the higher drug-to-albumin ratio and is not predicted by Mehtala's PEGylation work, which achieves site-specific, homogeneous conjugation at Cys-34 without partial reduction. The Action's routine optimization rationale assumes that increasing or decreasing the drug-to-albumin ratio would produce predictable, proportional changes in outcome. The specification demonstrates the opposite. The transition from a DAR of 1 to a DAR of 3 introduces structural heterogeneity and altered release kinetics that are qualitatively different from the behavior of the 1:1 conjugate.
The unexpected results of the 1:1 ratio extend beyond in vitro structural and release data to in vivo pharmacokinetics. The specification discloses a direct, quantitative comparison among ALDC1, ALDC3, and MMAE-MAL (the in vivo albumin-binding prodrug of Kim). As noted above, the AUC (area under the curve, i.e., total drug exposure in plasma over time) of total MMAE in ALDC1 group was significantly higher, which was 160% of that in MMAE-MAL group and 200% of the ALDC3 group. This finding can be due to premature cleavage and rapid clearance of MMAE in the MMAE-MAL and ALDC3 groups. Here, in both MMAE-MAL and ALDC3 arms, MMAE was more susceptible to being cleaved and prematurely released in the plasma, resulting in faster clearance than the ALDC1 group.
The fact that ALDC1 achieves a 100% improvement in total drug exposure over ALDC3, a conjugate that differs only in its drug-to-albumin ratio, is a result that a person of ordinary skill in the art would not have predicted from the prior art. The Action's routine optimization rationale provides no basis for predicting that a 3-fold reduction in drug loading (from DAR 3 to DAR 1) would double the total plasma drug exposure. This is precisely the type of result that is "different in kind and not merely in degree from the results of the prior art."
As such, Applicant contends that the claims are not obvious over the combination of Mehtala, Kim, and Bradbury, as evidenced by Buckel. Therefore, reconsideration and withdrawal of the rejection is respectfully requested.
Examiner’s Explanations:
Applicants’ arguments have been fully considered but are not deemed persuasive for the following reasons. First, Applicants’ allegation that Kim's entire system is built upon a fundamentally different principle of operation from that claimed, is moot because contrary to Applicants’ allegation, Kim et al. teach a chemotherapeutic prodrug conjugate comprising: an albumin-binding moiety such as maleimide, which is joined through a caspase 3-cleavable peptide linker, which is conjugated to a chemotherapeutic agent MMAE, while Bradbury et al. teach a cathepsin-B cleavable valine-citrulline dipeptide linker (see column 19, lines 13-15). As such, it would have been obvious to a POSITA that use of a cleavable linker provides site-specific payload release within tumor cells, thereby reducing toxic effects on normal cells that are neighboring cancer cells as noted above. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicants’ arguments regarding how the claimed composition is made by a different process, i.e., conjugated ex vivo and therefore there is unexpected property of the claimed composition associated with it, is moot because the patentability of the composition solely rests on the structure of the composition, and does not depend on how it is made (italicized for added emphasis). Therefore, the teachings of prior art read on the structure of the claimed composition regardless of whether it is made in vivo or ex vivo, and the claims do not recite any additional limitations that differentiate how the claimed composition is different structurally when it is made in vivo or ex vivo.
Likewise, Applicants’ argument regarding the use of controlled reduction method to expose a limited number of thiols from the total 17 disulfide bonds present in albumin is moot because the patentability of the composition solely rests on the structure of the composition and not on the process used to make the claimed composition. In addition, the number of free thiols is not a claim limitation recited in the claimed composition. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., number of free thiols) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Furthermore, Applicants’ argument regarding site-specific loading of drug to albumin at 1:1 ratio allowed the conjugate to maintain the native structure of albumin and its intrinsic properties, is moot because in accordance with MPEP 2144.05 “Optimization & Result Effective Variables”, changing the ratio of drug-to-albumin is considered a result-effective variables which can be optimized, especially when a Mehtala et al. optimized the ratio for a different drug to albumin, i.e., 5:1 or 10:1, and this particular parameter is therefore recognized in the relevant art as a result-effective variable, i.e., a variable which achieves a recognized result. Therefore, the determination of the optimum or workable ranges for such a variable is characterized as routine experimentation. In conclusion, a POSITA would have recognized that optimization of drug-to-albumin ratio can be done through a routine experimentation (italicized for added emphasis).
Contrary to Applicants’ allegation that neither Mehtala nor Kim discloses or predicts this structural consequence of increasing the drug-to-albumin ratio, and that it is an unexpected consequence of the specific combination of site-specific conjugation at Cys-34 and a 1:1 loading ratio that avoids the disulfide bond disruption required to achieve higher DARs, it would have been obvious for a POSITA to make and use the claimed composition based on the teachings of Mehtala et al. especially when Mehtala et al. demonstrated the site-specific conjugation at Cys-34 of albumin to a linker-drug while optimizing drug-to-albumin ratio.
Lastly, Applicants’ arguments regarding ‘the unexpected results of the 1:1 ratio’ is moot because such are inherent characteristics of the composition made from the combined teachings of Mehtala et al., Kim et al. and Bradbury et al. when optimized to 1:1 ratio. The composition taught by the combined references of Mehtala et al., Kim et al. and Bradbury et al. directly read on Applicants’ claimed composition. Furthermore, even though Applicants mention the experimental data found in the instant specification in order to argue ‘unexpected results’, such are not part of the claimed limitation. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
For the reasons provided herein, the invention as claimed is prima facie obvious over the combined teachings of the prior art.
Examiner Note:
The reference of JP 2017506628 A is noted herein because this reference also teaches a prodrug conjugate comprising albumin to MMAE via covalent bond (see claims).
Conclusion
Claims 1-2, 4-5, 7-10, 12, 15-16, 18-19, 21-22 and 89-92 are rejected for the reasons as stated above. Applicants must respond to the objections/rejections in this Office action to be fully responsive in prosecution.
THIS ACTION IS MADE FINAL. 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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAE W LEE whose telephone number is (571)272-9949. The examiner can normally be reached on M-F between 9:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571)272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAE W LEE/
Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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