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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 12/23/2022, is a 371 of PCT/EP2021/066985, filed 06/22/2021 and claims foreign priority to PCT/EP2020/069341, filed 07/09/2020, and NL2025898, filed 06/24/2020.
Status of Application, Amendments, and/or Claims
Applicant’s response of 12/29/2025 is acknowledged. Claims 22, 34, and 39 are amended and claims 1-21 and 38 are cancelled. Claims 22-37 and 39-40 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 09/03/2025,
Claim 38 was rejected under 35 USC 112(b), 35 USC 112(d), 35 USC 103, and on the grounds of nonstatutory double patenting. The cancellation of the claim has rendered the rejections moot and the rejections are withdrawn.
Claim 39 was rejected under 35 USC 112(b). Applicant’s amendment to the claim to clarify that the conjugate is the ADC or AOC and to recite “an active pharmaceutical ingredient” in place of “one or more” has overcome the rejections and the rejections are withdrawn.
The following grounds of rejections are modified as necessitated by applicant’s amendment to the claims.
Claim Rejections - 35 USC § 103
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 22-23, 26-37, and 39-40 are rejected under 35 U.S.C. 103 as being unpatentable over Heisler, I., et al (2005) Combined application of saponin and chimeric toxins drastically enhances the targeted cytotoxicity on tumor cells Journal of Controlled Release 106; 123-127 in view of US 2015/0337042 A1 (Reilly, E.B., et al) 26 Nov 2015 and US 5,977,081 (Marciani, D.J.) 2 Nov 1999.
Heisler teaches that immunotoxins have to be administered in high doses due to low cytosolic uptake with the consequence of severe side effects. Recently, it was found that the cytotoxic activity from Agrostemma githago seeds can be attributed to a synergistic toxicity of a triterpenoid saponin and a ribosome-inactivating protein. Heisler investigates whether saponins are able to enhance the efficacy of a receptor-specific chimeric toxin consisting of saporin-3, epidermal growth factor, and a molecular adaptor previously shown to reduce side effects on non-target cells. Heisler teaches that pre-applied saponin enhances the target cell-specific cytotoxic effect, dependent on the cell line, between 3560- and 385,000-fold with an IC50 up to 0.67 pM. Non-target cells were not affected at the same concentration. At the optimal concentrations of the chimeric toxin and saponin, application of either one of the components alone showed no cytotoxicity at all proving a synergistic effect when combined. In the presence of saponin, ligand-free saporin-3 does not exhibit any cytotoxic effect up to 0.1 nM, providing further evidence for an increased specificity. This synergistic effect is in the same order of magnitude as in a mouse model. Heisler concludes that the investigations clearly demonstrate that combined administration of saponin and chimeric toxins open up a promising perspective for tumor therapy (abstract).
Heisler teaches that chimeric toxins (CT) are targeted toxins for tumor therapy comprising recombinant proteins or chemically coupled conjugates in which a cell-targeting moiety is combined with a cytotoxic agent. The latter is either a small radioactive molecule, a low molecular weight organic compound, or the catalytic domain of a natural toxin. Usually, the cell-targeting moiety is a natural ligand or an antibody fragment for cancer associated endocytic surface antigens. Heisler further teaches that typical target antigens include the epidermal growth factor (EGF) receptor, the proto-oncogene receptor ErbB-2, also known as HER-2 in humans, the interuleukin-2 receptor, or cancer associated carbohydrates (paragraph bridging pages 123-124).
Heisler teaches that an improvement for recombinant CTs was the development of a molecular adapter linking the toxic and targeting moiety. Due to cleavable endosomal and cytosolic peptides, the adapter mediates cytosolic trapping of the toxin, which leads to reduced side effects on non-target cells in vitro (page 124, left column, paragraph 3).
Heisler teaches that saponins are a highly diverse group of glycosides containing either a steroidal or triterpenoid aglycone to which one or more sugar chains are attached. The adjunctive-active properties of saponins were recognized as early as the 1920s. Heisler further teaches saponins from the bark of Quillaja Saponaria Molina (soap bark tree) has found successful application as an adjuvant for vaccination (page 124, right column, paragraph 2).
In the study performed by Heisler, cytotoxicity of chimeric toxins was tested in combination with saponium album from Gypsophila paniculata L. (Spn), which is structurally closely related to agrostemmasponin. Both agrostemmasporing and gypsoside, the main saponin of saponin album, are bisdesmosidic triterpene saponins with two branched sugar chains. One glycosidic sugar moiety is attached at pos. 3; the other sugar chain is attached via an ester bond at pos. 28 of the aglycone gypsogenin. The structure of gypsosid is shown in Fig. 1A, which is duplicated below for convenience (page 124, right column, paragraph 3; page 125, Fig. 1A). In the gypsosid of Heisler, the aldehyde functional group at position C23 is unmodified.
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The chimeric toxin used in the study performed by Heisler comprised an N-terminal 6x His-tag, saporin-3, the adapter and EGF. The adaptor is composed of a cytosolic cleavable peptide (page 126, left column, paragraph 2).
Heisler teaches that, in the studies performed, non-toxic concentrations of saponin were able to enhance the specific cytotoxicity of saporin-3 containing CTs dependent on the cell line, 3560- to 385,000-fold. A receiver operating characteristics analysis showed that saponin treatment not only decreased the required amount of the CT, but also leads to higher sensitivity and specificity, resulting in a broader therapeutic window (page 135, paragraph bridging columns). Heisler further discusses the potential mechanisms relating to this synergistic effect and teaches that, if saponin elongates the retention period of endocytosed proteins inside the endosomes, the probability for adapter toxins to cross the endosomal membrane is enhanced (page 13, right column, paragraph 2). As Heisler teaches that the gypsoid is able to enhance the probability of the toxin to cross the endosomal membrane, one of ordinary skill in the art would reasonably identify the saponin as being one that enhances endosomal escape allowing for higher accumulation in the cytosol of the cell. Additionally, the ability of the saponin to act as an endosomal escape enhancer is inherent to the structure of the saponin, and the scientific explanation of the prior art’s functioning does not render the old composition patentably new. See MPEP 2112 (I).
Heisler, however, does not disclose that the saponin is covalently conjugated to a sdAb via a cleavable linker as claimed.
US’042 teaches anti-epidermal growth factor (EGFR) antibodies and antibody drug conjugates (ADCs) including compositions and methods of using said antibodies and ADCs (abstract).
US’042 teaches that the disclosed anti-EGFR antibodies may be conjugated to a drug moiety to form an anti-EGFR antibody drug conjugate which increases the antibodies therapeutic efficacy in the treatment of cancer due to the ability of the ADC to selectively deliver one or more drug moieties to target tissues, such as a tumor associated antigen, e.g., EGFR expressing tumors (page 22, [0198]). Anti-EGFR ADCs of the invention comprise an anti-EGFR antibody, i.e., an antibody that specifically binds to EGFR, and delivers the conjugated drugs internally to a transformed cancer cell expressing EGFR (page 22, [0199]). Teachings which indicate that the ADCs transport conjugated drugs from the outside to inside of cells. US’042 further teaches that known ligands of EGFR include EGF (page 1, [0004]).
US’042 teaches the ADC has the following formula Ab-(L-D)n; where Ab is the antibody, e.g., anti-EGFR antibody, (L-D) is a linker-drug moiety, and n is an integer ranging from 1 to 20 (page 23, [0201]).
US’042 further teaches that the antibody or antigen binding portions thereof include a Fab, a Fab’, a F(ab’)2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody, or a diabody (page 20, [174]).
US’042 teaches that the linker may include one conjugating component or may include a spacer, which is a moiety that extends the drug linkage to avoid, for example, shielding the active site of the antibody or improving the solubility of the ADC (page 33, [0303]).
US’042 further teaches that linkers are preferably stable extracellularly in a sufficient manner to be therapeutically effective. Before transport or delivery into a cell, the ADC is preferably stable and remains intact, i.e., the antibody remains conjugated to the drug moiety. Linkers that are stable outside the target ell may be cleaved at some efficacious rate once inside the cell. Thus, an effective linker will: (i) maintain the specific binding properties of the antibody; (ii) allow intracellular deliver of the drug moiety; and (iii) maintain the therapeutic effect of the drug moiety (page 34, [0311]).
Suitable linkers include, for example, cleavable and non-cleavable linkers. A linker may be a “cleavable linker,” facilitating the release of a drug. Nonlimiting exemplary cleavable linkers include acid-liable linkers, e.g., comprising hydrazone (page 33, [0310]). The linker is cleavable under intracellular conditions, such that the cleavage of the linker sufficiently releases the drug from the antibody in the intracellular environment to be therapeutically effective. In some embodiments, the cleavable linker is pH sensitive, i.e., sensitive to hydrolysis at certain pH values. Typically, the PH sensitive linker is hydrolysable under acidic conditions. For example, an acid-liable linker that is hydrolysable in the lysosome, such as a hydrazone, can be used. Such linkers are relatively stable under neutral pH conditions, such as those of the blood, but are unstable at below pH 5.5 or 5.0, the approximate pH of the lysosome. In certain embodiments, the hydrolysable linker is a thioether linker, such as a thioether attached to the therapeutic agent via an acylhydrazone bond (page 34, [0312]).
US’042 further teaches that linkers can include non-peptide polymers including, for example, polyethylene glycol (page 41, [0366)].
US’042 teaches pharmaceutical compositions comprising the ADCs disclosed and a pharmaceutically acceptable carrier (page 50, [0416]). Supplementary active compounds can also be incorporated into the compositions. Such combination therapies may advantageously utilize lower dosages of the administered therapeutic agents, thus avoiding possible toxicities or complications associated with the various monotherapies (page 53, [0439]). US’042 further teaches that the compositions comprising the antibodies and antibody portions may further comprise an agent useful as an adjuvant, such as those used to increase the absorption or dispersion of a therapeutic protein (page 53, [0433])
US’042 teaches that conjugation of the drug to the antibody via a linker can be accomplished by any technique known in the art. A number of different reactions are available for covalent attachment of drugs to linkers and linkers to antibodies. This may be accomplished by reaction of the amino acid residues of the antibody, including the amine groups of lysine, the free carboxylic acid groups of glutamic and aspartic acid, the sulfhydryl groups of cysteine and the various moieties of the aromatic amino acid (page 41, [0368]).
US’081 teaches a triterpene saponin-lipophile conjugate, comprising a nonacylated or deacylated triterpene saponin that includes a 3-glucornic acid residue; a lipophilic moiety; wherein said saponin and said lipophilic moiety are covalently attached to one another, either directly or through a linker group and wherein said attachment occurs through a covalent bond between the carboxyl carbon of said 3-glucuronic acid residue and a suitable functional group on the lipophilic group or the linker group (column 39, claim 1). An example of the binding taught by US’081 is shown in the image below (column 41, claim 21):
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US’081 further teaches that the triterpene saponin has a triterpene aglycone core structure with branched sugar chains attached to positions 3 and 28 (column 39, claim 2) and that the triterpene saponin has a quillaic acid or gypsogenin core structure (column 40, claim 3). US’081 further teaches that the conjugate comprises a linking group that forms a bond between the 3-glucuronic acid residue of the triterpene saponin and a second functional group that forms a bond with a reactive functional group on the lipophilic residue (column 40, claim 18). US’081 further teaches that the lipophilic moiety is selected from a group which includes polyethylene glycol (column 42, claim 26). US’801 teaches that the conjugation of the saponin to the lipophilic moiety makes the saponin easier to purify, less toxic, chemically more stable, and possess equal or better adjuvant properties than the original saponin (abstract).
US’081 teaches pharmaceutical compositions comprising one or more saponin conjugations and a pharmaceutically acceptable carrier or diluent as well as compositions that further comprise an additional agent such as an antigen (column 42, claims 27-28).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by Heisler to further conjugate the saponin to an anti-EGFR antibody using the antibody and linkers taught by US’042 using the conjugation techniques taught by US’081. An ordinarily skilled artisan would have been motivated to conjugate the saponin of Heisler to an antibody in order to gain the advantage of targeted delivery of the saponin to target cells using a targeting moiety, such as a single domain antibody, as taught by US’042. An ordinarily skilled artisan would have been motivated to use an EGFR antibody specifically as the cytotoxic saporin conjugate taught by Heisler targets EGFR indicating that both the saponin and the saporin would be targeted to the same cells. It would have been obvious to conjugate the antibody and linker to the saponin using the methods disclosed by US’081, which demonstrates conjugation of similar structures, such as polyethylene glycol, to saponins that have overlapping structures with the saponin used by Heisler. An ordinarily skilled artisan would have had a reasonable expectation of success as US’081 demonstrates methods that can be used to successfully conjugate linkers, as well as polyethylene glycol, to saponin while maintaining, or even improving, therapeutic efficacy.
Regarding claim 38, as discussed in detail above, US’042 teaches an antibody drug conjugate with the formula Ab-(L-D)n; where Ab is the antibody, L is a linker, D is a drug moiety, and n ranges from 1 to 20 (page 34, [0322]). US’042 further teaches that n can be from 1 to 4 (page 23, [0201]). Such a structure meets the instant claim limitation where u1 is 1, n is 0 to 4, m1 is 0, u2-u4 are 0, p is 0, q1 is 0, m2 is 0, q2 is 0, r is 0, t is 0, and v is 0.
Regarding claim 39, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the EGF ligand in the chimeric toxin taught by the combination of Heisler, US’042, and US’081 with an EGFR antibody based on the teachings of US’042, forming an antibody-drug conjugate (ADC). It would have been obvious to make this substitution as EGF is a known ligand of EGFR, as taught by US’042, indicating that the EGF of Heisler and the EGFR antibody of US’042 target the same receptor. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Regarding claim 40, the combination of Heisler, US’042, and US’081 teach the pharmaceutical combination of claim 23 as discussed in detail above. These compositions represent the active components of the claimed kit. The inclusion of instructions in a kit is not considered a novel step in the case where no functional relationship exists between the printed matter and the product. See MPEP 2111.05 (b). As there is no functional relationship between the compositions and the instructions of the kit claimed in the instant application, that is to say that the instructions outlined in claim 40 do not add additional functionality (structure) to the active components in the kit, the inclusion of instructions in claim 40 is not considered a novel step.
Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Heisler, I., et al (2005) Combined application of saponin and chimeric toxins drastically enhances the targeted cytotoxicity on tumor cells Journal of Controlled Release 106; 123-127 in view of US 2015/0337042 A1 (Reilly, E.B., et al) 26 Nov 2015 and US 5,977,081 (Marciani, D.J.) 2 Nov 1999 as applied to claim 22 above, and in further view of Nessler, I., et al (2020) Increased tumor penetration of single-domain antibody drug conjugates improves in vivo efficacy in prostate cancer models Cancer Res. 80(6); 1268-1278.
The combination of Heisler, US’042, and US’081 teach the conjugate of claim 22 as discussed in detail above.
The combination of applied references, however, does not disclose that the single domain antibody is a VH domain derived from a heavy chain of an antibody, a VL domain derived from the light chain of an antibody, or a VHH domain, or that the conjugate comprises at least two sdAbs.
Nessler teaches that antibody-drug conjugates have opened a new field of targeted therapeutics based on “hybrid” drugs combining desirable targeting properties of biologics with the potency of small molecule cytotoxic payloads. For ADCs, the protein carrier is typically a monoclonal antibody that specifically binds to a target antigen expressed on cancer cells, increasing the delivery of the small molecule payload to the site of action in vivo. However, a drawback of antibodies is slow tumor penetration. The tumor uptake of antibodies is limited by their extravasation rate and they tend to penetrate only a few cell layers outside of blood vessels due to their rapid antigen binding rate relative to intratumoral diffusion. In the clinic, unconjugated antibodies are often well tolerated, such that they can be delivered at very high doses that saturate receptors on cell layers closer to the blood vessel, enabling the antibody to diffuse farther through the tumor. However, the payload toxicity of ADCs limits the dose and frequency of administration, restricting tumor penetration depths and allowing regrowth between doses (page 2 paragraph 1).
Some smaller scaffolds are already being tested in the clinic including bivalent single-domain antibodies (page 3, paragraph 1). In the work presented by Nessler, the tumor tissue pharmacokinetics and efficacy of 3 different PSMA-binding single domain antibody (Humabody) drug conjugates and an IgG drug conjugate was tested. Humabodies are fully human, single heavy chain variable (VH) domains generated using a proprietary transgenic mouse platform. The mice lack murine heavy chain, and light chain expression, but contain human heavy chain genes. After in vitro maturation and development, multiple VH domain Humabodies can be constructed with a range of functionality to optimize target engagement and improve therapeutic benefit. Nessler used this platform to test the impact of two main design parameters with the ADCs: the cellular internalization rate and the plasma clearance rate. The first construct, VH2-VH1-HLE is a fusion between three VH domains: two PSMA binding domains to two different epitopes conjugated to an albumin binding half-life extender VH domain. Targeting multiple epitopes results in antigen cross-linking and rapid internalization, while binding albumin can slow plasma clearance. The second construct consisted of a monovalent binding domain, VH2, connected via a linker to the albumin-binding domain, and the third consisted of VH2-VH1, without the addition of the half-life extender (page 3, paragraph 2).
Nessler concludes that single-domain antibodies provide a promising platform for controlling the internalization kinetics, binding affinity, size, and plasma clearance of ADC constructs. While the use of a variable heavy chain binding domain provides improved transport characteristics, e.g., blood vessel permeability and diffusion (page 13, paragraph 2).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the conjugate taught by the combination of Heisler, US’042, and US’081 to use a variable heavy chain derived from the anti-EGFR antibody heavy chain based on the teachings of Nessler. It would have further been obvious to include at least two sdAbs linked to the saponin in the conjugate based on the teachings of Nessler. An ordinarily skilled artisan would have been motivated to use a variable heavy chain as the sdAb and to include at least two sdAbs conjugated to the saponin as Nessler teaches that such sdAbs improve the transportation characteristics of ADCs including permeability and diffusion. An ordinarily skilled artisan would have had a reasonable expectation of success as, like the combination of Heisler, US’042, and US’081, Nessler is teaching the use of ADCs for the treatment of cancer. Additionally, Nessler studied the prostate cancer, which is a cancer disclosed by US’042 that can be treated with the anti-EGFR conjugates (US’042, page 44, [0386]).
Response to Arguments
Applicant’s arguments in the response filed 12/29/2025 have been fully considered in so far as they apply to the rejections of the instant office action, but were not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that Heisler does not teach a cleavable linker or the conjugation of a saponin to a single domain antibody via an acid liable linker and that, to cure these deficiencies, US’042 and US’081 are cited.
Regarding US’042, applicant argues that the reference relates to the transport of a cytotoxic drug to tumor cells using an anti-EGFR antibody to target cells overexpressing EGFR. US’042; however, does not teach an sdAb conjugated to a saponin that can escape the endosomal membrane. Applicant further argues that US’042 lists a multitude of linker options from [0303] to [0370] in which acid liable linkers is embedded and that one of ordinary skill in the art would not be able to choose a suitable linker without any guidance apart from the exhaustive list provided. Applicant further argues that US’042 exemplifies anti-EGFR antibodies covalently linked via a pyrrolobenzodiazine, maleimidocaproyl, valine-citrulline, or p-aminobenzyloxycarbamyl linker, none of which are acid liable. Applicant argues that, even if US’042 does generally disclose acid-liable linkers, US’042 is silent with regard to the use of a saponin.
It is first noted that the rejection of record is not based on any single reference, but rather a combination of the applied references and what the combination references would have suggested to one of ordinary skill in the art prior to the effective filing date of the claimed invention. See MPEP 2145 (IV). As such, US’042 is not required to teach the use of saponin as this limitation is taught by Heisler.
Additionally, even if US’042 teaches various linkers that can be used to form conjugates, US’042 explicitly teaches acid-cleavable linkers for use in conjugates, including those that are relatively stable under neutral pH conditions, such as those in the blood, but are unstable at or below pH 5.5 or 5.0, the approximate pH of the lysosome (page 34, [0312]). As US’042 expressly teaches acid-cleavable linkers for use in antibody-drug conjugates, one of ordinary skill in the art would have been able to select and use the linkers with a reasonable expectation of success. Furthermore, while applicant argues that US’042 does not exemplify an acid liable linker, the requirement for obviousness is a reasonable expectation of success and conclusive proof of efficacy is not required. See MPEP 2143.02 (I). In this case, the teachings of US’042 demonstrate that acid liable linkers were known and studied in the art of antibody drug conjugation and an ordinarily skilled artisan would have reasonably been able to select such a linker with a reasonable expectation that the linker would be relatively stable under neutral pH conditions, such as those in the blood, but unstable at or below pH 5.5 or 5.0, the approximate pH of the lysosome, as taught by US’042.
While applicant further argues that one of ordinary skill in the art would not look to US’042 for any of the claimed elements, US’042 provides motivation for the conjugation of therapeutics, such as the saponin of Heisler, to an anti-EGFR targeting antibody. As discussed in the rejection, US’042 teaches that the conjugation of an antibody to a therapeutic selectively delivers the drug moieties to target tissues, such as a tumor associated antigen. The ADCs disclosed comprise an anti-EGFR antibody which delivers the conjugated drugs internally. Therefore, one of ordinary skill in the art would be motivated to further conjugate the saponin of Heisler to an antibody in order to gain the advantage of targeted delivery of the saponin to target cells using the targeting moiety, such as a single domain antibody. The conjugation of an EGFR targeting moiety is further motivated by the teachings of Heisler in which the cytotoxic saporin conjugate targets EGFR indicating that, by conjugating the saponin to an EGFR targeting moiety would result in both being targeted to the same EGFR overexpressing cells.
With regards to US’081, applicant argues that the conjugation chemistry of US’081 only relates to conjugation to the carboxylic acid off of the glucuronic acid, which is not applicable to other positions, such as the C-23 position of the saponin. Applicant further argues that US’081 merely teaches the conjugation of polyethylene glycol with an ethylamine side change to afford a carbamate, which is not acid liable. Applicant argues that US’081 fails to teach how to conjugate a single domain antibody via an acid-liable linker.
As discussed in detail above, the rejection is based on the combination of applied references and what the references would have suggested to one of ordinary skill in the art prior to the effective filing date. As such, US’081 does not need to expressly teach a single domain antibody or acid-liable linker as these limitations are met by the other reference, specifically US’042. Rather, US’081 is applied in the rejection to demonstrate that conjugation of moieties to saponins with overlapping structures to those taught by Heisler were known and demonstrated in the art.
Additionally, while the conjugation of US’081 is to the carboxylic acid off of the glucuronic acid and may not be applicable to other positions, such as the C-23 position of the saponin, the instant claims do not require that the conjugation be to the C-23 position of the saponin. Rather, independent claim 1 recites the limitation “wherein an aldehyde functional group present at position C23 of the aglycone core structure is either chemically unmodified or is involved in covalent binding of the cleavable linker”. As such, the claims do not require that the aldehyde functional group at position C23 be involved in the binding of the cleavable linker as the functional group at this position can, alternatively, be chemically unmodified. Therefore, in the broadest reasonable interpretation of the claim, the saponin can be conjugated in any position, including the carboxylic acid off of the glucuronic acid taught by US’081. It is noted that instant claim 34 further supports this interpretation, claiming that the glucuronic acid in a first saccharide chain at the C3beta-OH group of the aglycone core structure is involved in the covalent binding. Additionally, the claims do not require that the conjugated saponin have any specific structure, or that any specific reagents be used to form the conjugation and; therefore, conjugation of the acid cleavable linker to the saponin using any method known in the art would meet the instant claim limitations.
With regards to the rejection of claims 24 and 25, applicant argues that none of Heisler, US’042, or US’081 references alone, or in combination teach the use of sdAb. This however, is not the case. US’042 expressly teaches that the antibodies, or antigen binding portions thereof in the conjugates can comprise a single domain antibody. In the rejection of claims 24 and 25, the reference Nessler is applied to demonstrate that it would have been obvious to use single domain antibodies in the format of a VH domain derived from a heavy chain of an antibody, a VL domain derived from the light chain of an antibody, or a VHH domain, or that the conjugate can comprise at least two sdAbs.
Applicant further argues that the rejection fails to consider the cited references in their entirety, including portions that lead away. Applicant cites Nessler at 1275, right column, first paragraph as teaching that one of the disadvantages of using single-domain antibodies or other small protein scaffolds in places of antibodies is rapid clearance teaching that VH2-VH1-AF680 demonstrated poor tumor uptake caused by rapid kidney filtration. Applicant argues that, to overcome this problem, Nessler teaches conjugation of an albumin-binding domain to the sdAb to extend plasma half-life, increasing the molecular weight and enabling better penetration.
While Nessler teaches that a potential disadvantage of using single-domain antibodies is rapid clearance, and teaches that the addition of an albumin binding domain can extend plasma half-life, this alone does not teach away from the use of sdAbs in antibody drug conjugates because the teaching does not criticize, discredit, or otherwise discourage the use of an sdAb in conjugates.
Furthermore, the instant claims use comprising language with regards to the recited conjugate components. The instant disclosure defines “comprising” on pages 12-13 stating that “The term ‘comprising’, used in the claims, should not be interpreted as being restricted to for example the elements or method steps or the constitutions of a composition listed thereafter; it does not exclude other elements or method steps or constituents in a certain composition. it needs to be interpreted as specifying the presence of the stated features, integers, (method) steps or components as referred to, but does not preclude the presence or addition of one or more other features, integers, steps or components, or groups thereof”. A definition which is in line with that of MPEP 2111.03 (I).
As such, the conjugates could further comprise an albumin binding domain to extend plasma half-life and such an inclusion would still meet the instant claim requirements.
That said, Nessler concludes that single-domain antibodies provide a promising platform for controlling the internalization kinetics, binding affinity, size, and plasma clearance of ADC constructs (page 13, paragraph 2) and, in the in vitro and in vivo efficacy studies provided, for instance in Fig. 1, demonstrates that all conjugates, including those without the half-life extension domains, were capable of reducing tumor volume.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
18/012,760
Claims 22-37 and 39-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-9, 11-14, 17, 21-26, and 54 of copending Application No. 18/012,760 in view of Heisler, I., et al (2005) Combined application of saponin and chimeric toxins drastically enhances the targeted cytotoxicity on tumor cells Journal of Controlled Release 106; 123-127 in view of US 2015/0337042 A1 (Reilly, E.B., et al) 26 Nov 2015 and US 5,977,081 (Marciani, D.J.) 2 Nov 1999 and Nessler, I., et al (2020) Increased tumor penetration of single-domain antibody drug conjugates improves in vivo efficacy in prostate cancer models Cancer Res. 80(6); 1268-1278.
App’760 claims a therapeutic combination comprising a first pharmaceutical composition comprising a first binding molecule that is covalently bound to saponin, where the saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside; and a second composition comprising a conjugate with a second binding molecule different from the first covalently conjugated to an effector molecule where the compositions comprise pharmaceutically acceptable excipients or diluents (claims 1-2). App’760 further claims that the binding molecules are proteinaceous and the saponin is covalently bound to an amino acid residue of the binding molecule via a linker (claims 3-4). App’760 claims that the binding site are two epitopes of the same cell (claim 5). App’760 claims that the cell surface molecule is EGF and the binding molecules can consist of an immunoglobulin (claim 8, which is an antibody fragment including a single domain antibody such as a VHH or VH (claim 9). App’760 claims that the bidesmosidic triterpene saponin has an aldehyde function at position C23, and a first saccharide chain at the C3beta-OH group of the saponin comprising a glucuronic acid moiety and a second saccharide chain linked to C28 (claim 13) and is at least one of a saponin isolated from Gysophila species, a Saponaria species, an Agrostemma species, and a quillaja species (claim 14). App’760 further claims saponins that overlap with those of the instant claims (claim 20). App’760 further claims a kit comprising the combination (claim 54).
App’760 differs from the instantly claimed invention in that App’760 does not claim that the conjugate comprises an acidic conditions cleavable bond subject to cleavage under acidic conditions in endosomes and/or lysosomes. App’760 also does not claim that the sdAb binds to the instantly claimed antigens/receptors or that the effector molecule is dianthin or saporin.
The teachings of Heisler, US’042, US’081, and Nessler are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’760 with the teachings of Heisler, US’042, US’081, and Nessler to arrive at the instantly claimed invention. For instance, US’042 teaches the conjugates that target EGFR and the use of cleavable bonds that cleave under acidic conditions in lysosomes releasing the conjugated therapeutic; Heisler teaches that the administration of saponin and a targeted saporin conjugate provides synergistic outcomes; US’081 demonstrates conjugation to saponin; and Nessler demonstrates the use of two sdAbs. An ordinarily skilled artisan would have had a reasonable expectation of success in making these modifications as App’760 is drawn to targeted conjugates of saponins and the combination of Heisler, US’042, US’081, and Nessler all are teaching conjugates and delivery of therapeutics.
This is a provisional nonstatutory double patenting rejection.
18/012,710
Claims 22-37 and 39-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39-44 and 46-65 of copending Application No. 18/012,710 in view of Heisler, I., et al (2005) Combined application of saponin and chimeric toxins drastically enhances the targeted cytotoxicity on tumor cells Journal of Controlled Release 106; 123-127 in view of US 2015/0337042 A1 (Reilly, E.B., et al) 26 Nov 2015 and US 5,977,081 (Marciani, D.J.) 2 Nov 1999 and Nessler, I., et al (2020) Increased tumor penetration of single-domain antibody drug conjugates improves in vivo efficacy in prostate cancer models Cancer Res. 80(6); 1268-1278.
App’710 claims a conjugate for transferring a saponin from the outside of a cell into said cell, the conjugate comprising the saponin; and a single domain antibody capable of binding said cell, wherein the sdAb and the saponin are covalently bound via a linker; and wherein the saponin is a monodesmosidic triterpene glycoside or a bidesmosidic triterpene glycoside (claim 39). App’710 claims that the sdAb is a VH, a VL, or a VHH, and that the sdAb is covalently linked to the saponin (claims 40-41). App’710 claims that the conjugate comprises 1 to 100 saponin molecules; and has a structure that overlaps with those of the instant claims (claim 44 and 46-49). App’710 further claims that the linker is a cleavable linker that cleaves under acidic conditions in vivo; and that the linker further comprises an oligomeric or polymeric molecule that binds the saponin; and that the cleavable bond comprises a hydrazone bond (claim 57). App’710 claims that the sdAb binds to a tumor cell surface receptor (claim 59). App’710 claims a pharmaceutical composition which is also claimed to further include a second composition with an active pharmaceutical ingredient, as well as a method of treating a patient suffering from a disease and a method of transferring an active pharmaceutical composition into a cell, and a kit (claims 61-64). App’710 further claims that the single domain antibody is selected from a group which has overlapping targets with those of the instant claims (claim 65).
App’710 claims the features of the instantly claimed conjugate and it would have been obvious to arrive at the conjugate of claim 22 based on the claims of App’710. App’710 does not claim that the tumor cell surface receptor is selected from those recited in the instant claims or that the second active ingredient is an ADC or AOC that comprises diathin or saponin.
The teachings of Heisler, US’042, US’081, and Nessler are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’710 with the teachings of Heisler, US’042, US’081, and Nessler to arrive at the instantly claimed invention. For instance, Heisler and US’042 demonstrate EGFR as a tumor cell surface receptor that can be targeted with an ADC in combination with saponin for synergistic treatment of tumor cells. US’081 demonstrates conjugation to saponin, and Nessler demonstrates the use of sdAb, including at least 2, in conjugates for improved delivery of conjugated drugs. An ordinarily skilled artisan would have had a reasonable expectation of success as App’710 is drawn to targeted conjugates of saponins and the combination of Heisler, US’042, US’081, and Nessler all are teaching conjugates and delivery of therapeutics.
This is a provisional nonstatutory double patenting rejection.
18/012,723
Claims 22-37 and 39-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 57-77 of copending Application No. 18/012,723 in view of Heisler, I., et al (2005) Combined application of saponin and chimeric toxins drastically enhances the targeted cytotoxicity on tumor cells Journal of Controlled Release 106; 123-127 in view of US 2015/0337042 A1 (Reilly, E.B., et al) 26 Nov 2015 and US 5,977,081 (Marciani, D.J.) 2 Nov 1999 and Nessler, I., et al (2020) Increased tumor penetration of single-domain antibody drug conjugates improves in vivo efficacy in prostate cancer models Cancer Res. 80(6); 1268-1278.
App’723 claims a conjugate for transferring an effector molecule from outside of a cell into said cell comprising an effector molecule comprising an oligonucleotide, a sdAb capable of binding a cell surface molecule, and at least one saponin; where the effector molecule, the sdAb and the saponin are covalently bound to one another via a linker, and the saponin is mono-desmosidic triterpene glycoside or bi-desmosidic triterpene (claim 57). App’573 further claims that the sdAb is a VH, VL, or VHH domain, and that there are at least two sdAbs, wherein two sdAbs are the same or are capable of binding to the same binding site on the cell surface molecule (claims 58-59). App’573 further claims that the cell surface molecule is a tumor cell specific receptor and includes sdAbs recited in claim 61 which overlap with those of the instant claims (claims 61-62). App’723 further claims that the saponin has a structure overlapping with the structures of the instant claims and is bound to the aglycone core structure at position 23 (claim 65-71). App’723 further claims that the linker is an acid-sensitive linker, as well as pharmaceutical compositions and methods of treating diseases (claims 75-76).
App’723 differs from the instantly claimed invention in that App’723 claims a conjugate which comprises the saponin, sdAb, and an effector molecule in the same conjugate. App’723 does not claim that the second active ingredient is an ADC or AOC that comprises diathin or saponin.
The teachings of Heisler, US’042, US’081, and Nessler are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’723 with the teachings of Heisler, US’042, US’081, and Nessler to arrive at the instantly claimed invention. For instance, Heisler demonstrates EGFR as a tumor cell surface receptor that can be targeted with an ADC in combination with saponin for synergistic treatment of tumor cells and demonstrates saporin as an effective toxin for chimeric toxins. US’081 demonstrates conjugation to saponin, and Nessler demonstrates the use of sdAb, including at least 2, in conjugates for improved delivery of conjugated drugs. An ordinarily skilled artisan would have had a reasonable expectation of success as App’723 is drawn to targeted conjugates of saponins and the combination of Heisler, US’042, US’081, and Nessler all are teaching conjugates and delivery of therapeutics.
This is a provisional nonstatutory double patenting rejection.
18/012,769
Claims 22-37 and 39-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 58-77 of copending Application No. 18/012,769 in view of Heisler, I., et al (2005) Combined application of saponin and chimeric toxins drastically enhances the targeted cytotoxicity on tumor cells Journal of Controlled Release 106; 123-127 in view of US 2015/0337042 A1 (Reilly, E.B., et al) 26 Nov 2015 and US 5,977,081 (Marciani, D.J.) 2 Nov 1999 and Nessler, I., et al (2020) Increased tumor penetration of single-domain antibody drug conjugates improves in vivo efficacy in prostate cancer models Cancer Res. 80(6); 1268-1278.
App’769 claims a saponin conjugate comprising at least one saponin covalently linked to a ligand for ASGPR, wherein the saponin is a monodesmosidic triterpenoid or a bidesmosidic triterpenoid saponin. App’769 further claims saponins which have structures overlapping with those of the instantly claimed invention (claims 59-61). App’769 further claims that the conjugate comprises 1-100 saponin molecules (claim 63); as well as pharmaceutical compositions comprising the conjugate and a second conjugate with an effector molecule (claims 64-66) which comprise a second or third conjugate of an effector moiety with a binding molecule that targets cell surface molecules that overlap with those of the instantly claimed invention (claim 74).
App’769 differs from the instantly claimed invention in that App’769 does not claim that the conjugate comprises an acidic conditions cleavable bond subject to cleavage under acidic conditions in endosomes and/or lysosomes. App’769 also does not claim that the effector molecule is dianthin or saporin.
The teachings of Heisler, US’042, US’081, and Nessler are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’769 with the teachings of Heisler, US’042, US’081, and Nessler to arrive at the instantly claimed invention. For instance, US’042 teaches the conjugates that target EGFR and the use of cleavable bonds that cleave under acidic conditions in lysosomes releasing the conjugated therapeutic; Heisler teaches that the administration of saponin and a targeted saporin conjugate provides synergistic outcomes; US’081 demonstrates conjugation to saponin; and Nessler demonstrates the use of two sdAbs. An ordinarily skilled artisan would have had a reasonable expectation of success in making these modifications as App’769 is drawn to targeted conjugates of saponins and the combination of Heisler, US’042, US’081, and Nessler all are teaching conjugates and delivery of therapeutics.
This is a provisional nonstatutory double patenting rejection.
17/312,193
Claims 22-37 and 39-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 7-11, 13-14, 16, 19, 26-30, 32-34, and 43 of copending Application No. 17/312,193 in view of Heisler, I., et al (2005) Combined application of saponin and chimeric toxins drastically enhances the targeted cytotoxicity on tumor cells Journal of Controlled Release 106; 123-127 in view of US 2015/0337042 A1 (Reilly, E.B., et al) 26 Nov 2015 and US 5,977,081 (Marciani, D.J.) 2 Nov 1999 and Nessler, I., et al (2020) Increased tumor penetration of single-domain antibody drug conjugates improves in vivo efficacy in prostate cancer models Cancer Res. 80(6); 1268-1278.
App’193 claims a first proteinaceous molecule comprising a first binding site provided with at least one covalently bound saponin bound via a linker and/or via an oligomeric or polymeric scaffold to an amino acid residue of the first proteinaceous molecule. Wherein the binding site comprises an immunoglobulin, or at least one binding domain of an immunoglobulin, or an antibody (claim 1). App’193 further claims saponin structures that overlap with those of the instantly claimed invention (claims 4, 7-10); as well as surface receptors that overlap with those of the instantly claimed invention (claim 11). App’193 further claims a combination with a second composition comprising a second conjugate (claim 14). App’193 claims that the first conjugate comprises between 1-100 saponins and that the at least one linker is a cleavable linker that is, for example, subject to cleavage under acidic conditions and comprises a hydrazone bond (claims 33-34).
App’193 claims the features of the instantly claimed conjugate and it would have been obvious to arrive at the conjugate of claim 22 based on the claims of App’193. App’193 does not claim that the tumor cell surface receptor is selected from those recited in the instant claims or that the second active ingredient is an ADC or AOC that comprises diathin or saponin.
The teachings of Heisler, US’042, US’081, and Nessler are as discussed above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’193 with the teachings of Heisler, US’042, US’081, and Nessler to arrive at the instantly claimed invention. For instance, Heisler and US’042 demonstrate EGFR as a tumor cell surface receptor that can be targeted with an ADC in combination with saponin for synergistic treatment of tumor cells. US’081 demonstrates conjugation to saponin, and Nessler demonstrates the use of sdAb, including at least 2, in conjugates for improved delivery of conjugated drugs. An ordinarily skilled artisan would have had a reasonable expectation of success as App’193 is drawn to targeted conjugates of saponins and the combination of Heisler, US’042, US’081, and Nessler all are teaching conjugates and delivery of therapeutics.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
In the response filed 12/29/2025, applicant requests that the rejections under nonstatutory double patenting be held in abeyance until otherwise allowable subject matter has been identified in the instant application.
As the nonstatutory double patenting rejections are not the only remaining rejections, the rejections are maintained.
Conclusion
No claims are allowed.
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.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693