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 .
Claim Status
Claims 1, 4, 8, 10, 15, 19-21, 24, 28, 38-42, 44, 46, 50-51, and 53 are pending and under examination in the instant office action.
Claim Objections
Claim 1 is objected to because of the following informalities: the recitation of "wherein the isolated polypeptide complex comprises at least one of the following characteristics" (lines 4-5) is informal because "comprising a characteristic" is not commonly used in the art to describe properties or characteristics. The examiner suggests amending to "wherein the isolated polypeptide complex has at least one of the following characteristics". Appropriate correction is required.
Claims 38-40 are objected to because of the following informalities:
Regarding claim 38-40, the claims recite “at least one cysteine residue is a free sulfhydryl”. This is informal because a cysteine by definition cannot be only a free sulfhydryl. The examiner suggest amending the claim to recite “one cysteine has a free sulfhydryl group” or “one cysteine comprises a free sulfhydryl”.
Claim 39 is informal for the recitation of “and at least one cysteine is selected from” because the article “the” is missing such that the claim does not clearly refer to the “one cysteine residue is a free sulfhydryl”. The examiner suggests amending the claim to recite “and the at least one cysteine is selected from” in line 2.
Regarding claim 40, there appears to be an inadvertent duplication such that claim 40 reads “and the at least one cysteine is selected from selected from” (emphasis is the examiner’s). The examiner suggests deleting one “selected from”.
Regarding claims 39 and 40, the claims recite “one cysteine selected from and corresponding to”. The “corresponding to” is duplicative and informal with “selected from”, the Examiner suggests striking “corresponding to”.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 41 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 41 is indefinite for the recitation of “wherein the at least one pair of cysteine residues comprises” followed by a list of eight pairs of cysteines joined by the conjunction “and” in line 6. It is unclear whether the claim therefore requires the “at least one pair of cysteines” to be all eight pairs or if the at least one pair may be selected from the recited group. The metes and bounds of the claim are therefore unclear.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 8, 10, 15, 19-21, 24, 28, 38-42, 44, 46, 50-51, and 53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 1, recitation of 80% identity to SEQ ID NO: 1 and 80% identity to SEQ ID NO: 2 allow for changes to the CDR within the VH and VL of the antibodies which are the binding determinant regions, but the art and genus of known species does not allow for predictable binding of the recited function of binding the targets CD3, PSMA, and albumin. Additionally, SEQ ID NO: 1 comprises a peptide mask which is required to bind the anti-CD3 scFv of SEQ ID NO: 1 in order to perform the masking function, but the art and genus of known species do not allow for predictable binding of mask/CD3 scFv binding; SEQ ID NO: 1 further comprises a protease cleavable sequence connecting the lifespan extension domain and mask to the anti-CD3 scFv, but the art and genus of species do not allow for predictable cleavage of any linker sequence by tumor-specific proteases.
Scope of the claimed genus
Claim 1 recites a genus of polypeptides comprising an antibody binding fragments which specifically binds to albumin, CD3, and PSMA, wherein SEQ ID NO: 1 comprises an anti-albumin VHH, a masking peptide binding to anti-CD3, a cleavable linker, an anti-CD3 scFv, and an anti-PSMA VL and SEQ ID NO: 2 comprises the corresponding anti-PSMA VH, but the claims allow for only 80% identity to SEQ ID NO: 2 and SEQ ID NO: 1 which allows for changing to the functionally determinant residues of SEQ ID NO: 1 and SEQ ID NO: 2 wherein the polypeptide comprises at least one of the following characteristics:
(a) at least one disulfide bond formed by a pair of cysteine residues in the first chain or the second chain or by a pair of cysteine residues in the first chain and the second chain;
(b) a secondary structure composition comprising a P-sheet or a random coil;
(c) at least one pyroglutamine in the second chain;
(d) a melting temperature (Tm) between of about 65 °C to about 85 °C when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0 mg/mL in a buffer comprising 10 mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3
(e) a far UV circular dichroism peak at a wavelength between 190 nm and 205 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.lmg/mL in 10mM potassium phosphate buffer pH 7.0;
(f) a far UV circular dichroism dip at a wavelength between 210 nm and 220 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.lmg/mL in 10mM potassium phosphate buffer pH 7.0; or
(g) a near UV circular dichroism peak at a wavelength between 250 nm and 300 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0mg/mL in a buffer comprising 10mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3.
The examiner notes that these limitations all relate to the folding, stability, and 3D or 2D structural characteristics of the peptide. However, each of these characteristics are determined by the primary sequence of the protein, and therefore it would not be predictable a priori which peptides of the genus of polypeptides comprising 80% identity to SEQ ID NO: 1 and 80% identity to SEQ ID NO: 2 would possess these characteristics.
State of the Relevant Art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “80% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
Additionally, 80% identity to SEQ ID NO: 1 allows for substitutions, additions, or deletions to up to 129 residues. This allows for changes to all 3 CDRs of the anti-albumin VHH, anti-CD3 scFv heavy and light chain CDRs, and all but 3 residues of the anti-PSMA VL, for example (129/132 Kabat CDR residues in SEQ ID NO: 1).
In regards to anti-CD3/anti-PSMA multispecific antibodies, other anti-CD3 and anti-PSMA antigen binding domains and multispecific antibodies comprising those binding domains are known in the art. For example, U.S. 20170051074 to Kirshner et. al. (Of record, IDS dated 6/28/2023) teaches anti-PSMA anti-CD3 bispecific antibodies and methods of using the bispecific antibody to induce T-cell proliferation and T-cell mediated killing of PSMA-expressing tumor cells (Abstract), wherein the anti-CD3 and anti-PSMA binding domains comprise different VH and VL CDRs than the instant VH/VL regions of SEQ ID NO: 1 and SEQ ID NO: 2. U.S. 20190169295 to Kufer et. al. (Of record, IDS dated 6/28/2023) teaches a binding molecule comprising three domains wherein one domain binds to a cell surface target molecule (e.g. PSMA, see Example 1), the second binding domain is capable to binding to the CD3 receptor complex, and the third binding domain is a binding domain is a binding domain which is capable of binding to serum albumin (Abstract).
Regarding tumor-protease activatable antibodies and antibody masking domains, some of these are known in the art. For example, WO2022098909 to Wesche et. al. teaches a peptide pro-drug comprising an albumin binding domain, an EpCAM binding domain, an anti-CD3 binding domain, a masking domain where the masking moiety masks the binding of the EpCAM or the CD3 binding domain [0018], and a cleavable linker [0041]. WO2016179003 to Dennis teaches bispecific antibodies comprising an anti-CD3 arm and an anti-tumor antigen arm and further comprising a masking moiety protecting the anti-CD3 binding domain connected by a cleavable moiety (Figure 4D).
Regarding properties a)-g), each of these is an inherent property of the protein determined by the primary sequence of the protein and the folding and post-translational modifications that occur during polypeptide production. For example, post-filing publication Harmalkar, Ameya, et al. "Toward generalizable prediction of antibody thermostability using machine learning on sequence and structure features." MAbs. Vol. 15. No. 1. Taylor & Francis, 2023 teaches a method of using a machine learning pipeline in order to predict point mutations for better thermostability. Although the authors note that experimental data is sparse, they teach “Further, for 18 out of 20 mutations, the SCNNs could identify the residue position correctly, albeit predicting different amino-acid mutations as most thermostable […] It is, therefore, remarkable that our networks could predict the thermostable residue positions in 90% of the cases, with 25% successful predictions (correct residue positions as well as amino-acid residues)” (p. 7 left column-right column). This demonstrates that it would have been unpredictable at the time of filing what residues are important for melting temperature of the instant polypeptide comprising VH/VL sequences, and the specification does not teach sufficient alternate polypeptides or structural information for a person of ordinary skill in the art to recognize the class of polypeptides with only 80% identity to SEQ ID NOs: 1 and 2 that possess the characteristics listed in features a)-g) regarding disulfide bonding, pyroglutamine formation, melting temperature in formulation, far UV circular dichroism peaks (e.g. recognizing the secondary structures found in the protein in formulation). Each of these features is affected by the primary sequence of the protein and therefore would have to be assessed as an inherent characteristic of the polypeptide for each polypeptide comprising primary sequence 80% identical to SEQ ID NOs: 1 and 2.
Summary of Species disclosed in the original specification
The instant specification discloses a single species of polypeptide consisting of SEQ ID NO: 1 and 2. The specification also refers to two versions of this polypeptide PC-1 v1 and PC-1 v2; however, any differences between the two polypeptides are not disclosed (e.g. Fig. 9 and 10). There are no particular alternate residues, deletions, or additions to SEQ ID NOs: 1 and 2 disclosed.
Do the disclosed species represent a genus?
MPEP §2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of variants to allow substitution, addition, or deletion of any amino acid in SEQ ID NOs: 1 and 2 that would preserve the anti-albumin, anti-CD3, anti-PSMA, tumor-protease cleavable linker, CD3 masking moiety functions or the particular physical characteristics discloses for the peptide consisting of the sequences identical to SEQ ID NO: 1 and 2.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by the disclosure of relevant, identifying characteristics; i.e. structure of other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet the requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity, protease substrate activity, and physical characteristics.
Although the instant specification characterizes some of the physical properties of SEQ ID NO: 1 and SEQ ID NO: 2 (e.g. Example 4, Fig. 9 show that the polypeptide of SEQ ID NO: 1 and 2 folds with a beta-sheet and random coil [0307-0308]). However, the specification does not disclose any relationship between the primary sequence of 80% identity to SEQ ID NO: 1 and SEQ ID NO: 2 as claimed and the characteristics disclosed, or discuss the relationship between the recited characteristics and the functions, such as binding, that are required of SEQ ID NO: 1 and SEQ ID NO: 2. As discussed in the state of the art section above, it would have been unpredictable for a person of ordinary skill in the art to determine how changes to the primary sequence would relate to the disclosed functions or the claimed properties of the peptide. Therefore, an artisan would not at once be able to envision all of the species with 80% identity to SEQ ID NOs: 1 and 2 that are within the scope of the claims and comprise the instant genus.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for antibody CDR residues for the recited function of binding the protein albumin, CD3, PSMA, or protease substrate or anti-CD3 masking functions. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; or iii) disrupt protein target binding. Further, there is a lack of species with alternate protease substrate sequences or anti-CD3 masking sequences. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polypeptide of claim 1 at the time of filing. Regarding claims 4, 8, 10, 15, 19,-21, 24, 28, 38, 39-42, 44, 46, 50-51, and 53 the claims are ultimately dependent on the rejected claim 1 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, 8, 10, 15, 19-21, 24, 28, 38-42, 44, 46, 50-51, and 53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a) making and using a polypeptide comprising SEQ ID NO: 1 and SEQ ID NO: 2 and b) A method of treating a PSMA-expressing cancer comprising administering to a subject having a cancer expressing PSMA the isolated recombinant polypeptide complex comprising a first and second chain comprising SEQ ID NO: 1 and SEQ ID NO: 2, does not reasonably provide enablement for a) any polypeptide complex comprising a first chain and a second chain with 80% identity to SEQ 1 and 2, respectively, wherein the polypeptide complex has particular characteristics as recited in claim 1 a)-g) and b) A method of treating any generic cancer comprising administering 80% identity to SEQ ID NO: 1 and 2. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. In In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) eight factors included for determining enablement:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The following is an analysis of these factors in relationship to this application.
Scope of the claims and nature of the invention
Claim 1 recites a genus of polypeptides comprising an antibody binding fragments which specifically binds to albumin, CD3, and PSMA, wherein SEQ ID NO: 1 comprises an anti-albumin VHH, a masking peptide binding to anti-CD3, a cleavable linker, an anti-CD3 scFv, and an anti-PSMA VL and SEQ ID NO: 2 comprises the corresponding anti-PSMA VH, but the claims allow for only 80% identity to SEQ ID NO: 2 and SEQ ID NO: 1 which allows for changing to the functionally determinant residues of SEQ ID NO: 1 and SEQ ID NO: 2 wherein the polypeptide comprises at least one of the following characteristics:
(a) at least one disulfide bond formed by a pair of cysteine residues in the first chain or the second chain or by a pair of cysteine residues in the first chain and the second chain;
(b) a secondary structure composition comprising a P-sheet or a random coil;
(c) at least one pyroglutamine in the second chain;
(d) a melting temperature (Tm) between of about 65 °C to about 85 °C when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0 mg/mL in a buffer comprising 10 mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3
(e) a far UV circular dichroism peak at a wavelength between 190 nm and 205 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.lmg/mL in 10mM potassium phosphate buffer pH 7.0;
(f) a far UV circular dichroism dip at a wavelength between 210 nm and 220 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.lmg/mL in 10mM potassium phosphate buffer pH 7.0; or
(g) a near UV circular dichroism peak at a wavelength between 250 nm and 300 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0mg/mL in a buffer comprising 10mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3.
The examiner notes that these limitations all relate to the folding, stability, and 3D or 2D structural characteristics of the peptide. However, each of these characteristics are determined by the primary sequence of the protein, and therefore it would not be predictable a priori which peptides of the genus of polypeptides comprising 80% identity to SEQ ID NO: 1 and 80% identity to SEQ ID NO: 2 would possess these characteristics.
Regarding claim 53, the claim is directed towards a method of treating any generic cancer comprising administering to a subject in need thereof the isolated recombinant polypeptide of claim 1.
State of the Relevant Art; level of ordinary skill; and level of predictability in the art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “80% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
Additionally, 80% identity to SEQ ID NO: 1 allows for substitutions, additions, or deletions to up to 129 residues. This allows for changes to all 3 CDRs of the anti-albumin VHH, anti-CD3 scFv heavy and light chain CDRs, and all but 3 residues of the anti-PSMA VL, for example (129/132 Kabat CDR residues in SEQ ID NO: 1).
In regards to anti-CD3/anti-PSMA multispecific antibodies, other anti-CD3 and anti-PSMA antigen binding domains and multispecific antibodies comprising those binding domains are known in the art. For example, U.S. 20170051074 to Kirshner et. al. teaches anti-PSMA anti-CD3 bispecific antibodies and methods of using the bispecific antibody to induce T-cell proliferation and T-cell mediated killing of PSMA-expressing tumor cells (Abstract), wherein the anti-CD3 and anti-PSMA binding domains comprise different VH and VL CDRs than the instant VH/VL regions of SEQ ID NO: 1 and SEQ ID NO: 2. U.S. 20190169295 to Kufer et. al. teaches a binding molecule comprising three domains wherein one domain binds to a cell surface target molecule (e.g. PSMA, see Example 1), the second binding domain is capable to binding to the CD3 receptor complex, and the third binding domain is a binding domain is a binding domain which is capable of binding to serum albumin (Abstract).
Regarding tumor-protease activatable antibodies and antibody masking domains, some of these are known in the art. For example, WO2022098909 to Wesche et. al. teaches a peptide pro-drug comprising an albumin binding domain, an EpCAM binding domain, an anti-CD3 binding domain, a masking domain where the masking moiety masks the binding of the EpCAM or the CD3 binding domain [0018], and a cleavable linker [0041]. WO2016179003 teaches bispecific antibodies comprising an anti-CD3 arm and an anti-tumor antigen arm and further comprising a masking moiety protecting the anti-CD3 binding domain connected by a cleavable moiety (Figure 4D).
Regarding properties a)-g), each of these is an inherent property of the protein determined by the primary sequence of the protein and the folding and post-translational modifications that occur during polypeptide production. For example, post-filing publication Harmalkar, Ameya, et al. "Toward generalizable prediction of antibody thermostability using machine learning on sequence and structure features." MAbs. Vol. 15. No. 1. Taylor & Francis, 2023 teaches a method of using a machine learning pipeline in order to predict point mutations for better thermostability. Although the authors note that experimental data is sparse, they teach “Further, for 18 out of 20 mutations, the SCNNs could identify the residue position correctly, albeit predicting different amino-acid mutations as most thermostable […] It is, therefore, remarkable that our networks could predict the thermostable residue positions in 90% of the cases, with 25% successful predictions (correct residue positions as well as amino-acid residues)” (p. 7 left column-right column). This demonstrates that it would have been unpredictable at the time of filing what residues are important for melting temperature of the instant polypeptide comprising VH/VL sequences, and the specification does not teach sufficient alternate polypeptides or structural information for a person of ordinary skill in the art to recognize the class of polypeptides with only 80% identity to SEQ ID NOs: 1 and 2 that possess the characteristics listed in features a)-g) regarding disulfide bonding, pyroglutamine formation, melting temperature in formulation, far UV circular dichroism peaks (e.g. recognizing the secondary structures found in the protein in formulation). Each of these features is affected by the primary sequence of the protein and therefore would have to be assessed as an inherent characteristic of the polypeptide for each polypeptide comprising primary sequence 80% identical to SEQ ID NOs: 1 and 2.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quantity of experimentation needed to make or use the invention based on the content of the disclosure
The instant specification discloses a single species of polypeptide consisting of SEQ ID NO: 1 and 2. The specification also refers to two versions of this polypeptide PC-1 v1 and PC-1 v2; however, any differences between the two polypeptides are not disclosed (e.g. Fig. 9 and 10). There are no particular alternate residues, deletions, or additions to SEQ ID NOs: 1 and 2 disclosed. The instant specification characterizes the instant species of PC-1 pharmacokinetic profile in non-human primates (NHPs) (Table 3, specification p. 59). The inventors demonstrate PC-1 has enhanced safety and pharmacokinetic properties relative to a non-masked version (TCE-1). The specification next disclosed the method of production and purification of PC-1 (Example 2). Lastly, the specification discloses additional properties of the purified product such as disulfide bond configuration (Example 3, [0305-0306], Table 4), secondary and tertiary structure determination by Far and Near-UV CD (Examples 4 and 5), and thermal stability analysis (Example 6).
Regarding methods of treatment comprising PC-1, the specification discloses a phase 1 clinical study design to determine the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of PC-1 administered to adult subjects with metastatic castration resistant prostate cancer (mCRPC) [0321-0322]. The instant specification also discloses a particular formulation of PC-1 at 2mg/mL in 10mM histidine, 8% (w/v) sucrose, 0.01% (w/v) polysorbate 20 (Table 5). It is also demonstrated in vitro that PC-1 is able to induce cytokine production in co-cultures of PBMCs or whole blood from healthy human donors [0335-0340]. There are no examples disclosed of PC-1 being used to treat any disease other than a PSMA-expressing cancer.
Conclusion
The Applicant does not have enablement for making and using any polypeptide complex comprising a first chain and a second chain with 80% identity to SEQ ID NOs: 1 and 2 with the particular characteristics claimed. The Applicant does not have enablement for a method of treating any generic cancer comprising administering to a subject in need thereof the recombinant polypeptide complex of claim 1 (claim 53). It would take an undue amount of experimentation to determine all polypeptides complexes comprising chains with 80% identity to SEQ ID NOs: 1 and 2 that perform the functions of binding PSMA, binding CD3, binding albumin, masking CD3, and acting as a tumor protease substrate, and to determine which of the polypeptide sequences have the inherent characteristics claimed with only partial identity to SEQ ID NO: 1 and 2. It would also take undue experimentation to determine a method of treating any generic cancer that does not express PSMA comprising administering the recombinant polypeptide complex of claim 1. Dependent claims are rejected for failing to resolve the scope of enablement as described.
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.
Claims 1, 4, 8, 10, 15, 19-21, 24, 28, 38-42, 44, 46, 50-51, and 53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 26 of U.S. Patent No. 11555078 (Of record, IDS dated 6/28/2023). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of '078 make obvious the instant claims as evidenced by as evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217 published 28 July 2013.
Regarding claims 1, 10, and 15, claims 1-26 of the ‘078 patent teach a polypeptide complex according to Formula I: A2-A1-L1-P1-H1 wherein A1 comprises a first antigen recognizing molecule that binds to an effector cell antigen, wherein A1 comprises an anti-CD3 binding molecule comprising complementary determining regions (CDRs) heavy and light chain SEQ ID NOs: 1-6; P1 comprises a peptide that binds to A1 of a particular formula as recited; wherein L1 comprises a linking moiety that connects A1 to P1 and is a substrate for a tumor specific protease; H1 comprises a half-life extending molecule; and A2 comprises a second antigen recognizing molecule that binds to PSMA (claim 1), wherein the polypeptide complex comprises the amino acid sequences according to SEQ ID NO: 72 and SEQ ID NO: 73 which are identical to instant SEQ ID NO: 1 and 2 as shown below:
Query Match 100.0%; Score 3414; Length 645;
Best Local Similarity 100.0%;
Matches 645; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGSTFYTAVMGWVRQAPGKGLEWVAAIRWTALTTSY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGSTFYTAVMGWVRQAPGKGLEWVAAIRWTALTTSY 60
Qy 61 ADSVKGRFTISRDGAKTTLYLQMNSLRPEDTAVYYCAARGTLGLFTTADSYDYWGQGTLV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDGAKTTLYLQMNSLRPEDTAVYYCAARGTLGLFTTADSYDYWGQGTLV 120
Qy 121 TVSSGGGGSGGGSGGVYCGPEFDESVGCMGGGGSGGGLSGRSDAGSPLGLAGSGGGSEVQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TVSSGGGGSGGGSGGVYCGPEFDESVGCMGGGGSGGGLSGRSDAGSPLGLAGSGGGSEVQ 180
Qy 181 LVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYA 240
Qy 241 DSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 DSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTV 300
Qy 301 SSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 SSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPG 360
Qy 361 QAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 QAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGG 420
Qy 421 TKLTVLGGGGSDIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKTGKVPKFLIY 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 TKLTVLGGGGSDIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKTGKVPKFLIY 480
Qy 481 EASTLQSGVPSRFSGGGSGTDFTLTISSLQPEDVATYYCQNYNSAPFTFGPGTKVDIKRT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 EASTLQSGVPSRFSGGGSGTDFTLTISSLQPEDVATYYCQNYNSAPFTFGPGTKVDIKRT 540
Qy 541 VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK 600
Qy 601 DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 645
|||||||||||||||||||||||||||||||||||||||||||||
Db 601 DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 645
Query Match 100.0%; Score 1199; Length 226;
Best Local Similarity 100.0%;
Matches 226; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGVVQPGRSLRLSCAASGFAFSRYGMHWVRQAPGKGLEWVAVIWYDGSNKYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGGGVVQPGRSLRLSCAASGFAFSRYGMHWVRQAPGKGLEWVAVIWYDGSNKYY 60
Qy 61 ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCARGGDFLYYYYYGMDVWGQGTTVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCARGGDFLYYYYYGMDVWGQGTTVT 120
Qy 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
Qy 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 226
||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 226
The claims of ‘078 do not explicitly teach the characteristics:(a) at least one disulfide bond formed by a pair of cysteine residues in the first chain or the second chain or by a pair of cysteine residues in the first chain and the second chain; (b) a secondary structure composition comprising a P-sheet or a random coil; (c) at least one pyroglutamine in the second chain; (d) a melting temperature (Tm) between of about 65 °C to about 85 °C when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0 mg/mL in a buffer comprising 10 mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3 (e) a far UV circular dichroism peak at a wavelength between 190 nm and 205 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.1mg/mL in 10mM potassium phosphate buffer pH 7.0; (f) a far UV circular dichroism dip at a wavelength between 210 nm and 220 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.lmg/mL in 10mM potassium phosphate buffer pH 7.0; or (g) a near UV circular dichroism peak at a wavelength between 250 nm and 300 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0mg/mL in a buffer comprising 10mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3, the claims of the ‘078 patent are silent. However, each of the properties a)-g) are inherent properties of the polypeptide complex consisting of SEQ ID NO: 1 and 2, because a protein with the same primary structure would be expected to have the same secondary structure, tertiary structure, and post-translational modifications provided it is made in a mammalian cell type. In order to determine the meaning of the claims to polypeptide SEQ ID NO: 1 and 2, the specification was consulted (MPEP §804.B.1). The specification discloses that the polypeptide may be made by expression in a host-expression vector system, and that the host may be for example a microorganism or a mammalian cell selected from a list (Col. 65 lines 15-43; Col. 68 lines 40-60).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make the polypeptide complex using a mammalian host-expression vector system to benefit from a method of making the claimed polypeptide. As set forth in MPEP §2145 (II) “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”. Products of identical composition cannot have mutually exclusive properties. See MPEP § 2112. As evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217 ““the advanced mammalian folding, secretion and post-translational apparatus is capable of producing antibodies indistinguishable from those in the human body with least concerns for immunogenic modifications” (p. 5 right column, “Mammalian Cells” section ¶1, emphasis is the Examiner’s). Thus, a polypeptide complex of SEQ ID NO: 1 and SEQ ID NO: 2 with the characteristics a)-g) as claimed is made obvious by the claims of ‘078 because the polypeptide complex comprising SEQ ID NO: 1 and SEQ ID NO: 2 of ‘078 would inherently possess all of the recited characteristics when made in a mammalian host-expression vector system.
Regarding dependent claims 4, 8, 19, 20, 21, 24, 28, 38-42, 44, 46,and 50-51, as described for claim 1, each of these characteristics would be an inherent property of the polypeptide complex consisting of 100% identity to SEQ ID NO: 1 and SEQ ID NO: 2 provided the polypeptide complex was produced in mammalian cells in order to produce the same folding and post-translational modifications. Thus, the claims directed at the particular disulfide bonds and positions of disulfide bonds (claims 19, 20, 21, 24, 28, 39-41) or lack thereof as free sulfhydryl (claim 38), the secondary and tertiary structures and resultant far UV and near UV circular dichroism peaks (claim 42, 46, 50-51), and melting temperatures would be characteristics inherently possessed by a polypeptide complex that has the same folding and post-translational modifications as the instantly claimed polypeptide complex.
Regarding claim 53, the claims of ‘078 do not explicitly recite a method of treating cancer comprising administering to a subject in need thereof the isolated recombinant polypeptide complex of claim 1.
MPEP 804.B.1 teaches “In particular, when ascertaining the scope of the reference’s claim(s) to a compound, the examiner should consider the reference’s specification, including all of the compound’s uses that are disclosed. See Sun Pharm. Indus., 611 F.3d at 1386-88, 95 USPQ2d at 1801-02”. Thus, the disclosed uses in the specification of ‘078 were consulted. The specification teaches use of the polypeptide complex: “In some embodiments, are methods of treating cancer in a subject need in need thereof comprising administering to the subject an isolated polypeptide or polypeptide complex as described herein”. Therefore, claim 53 is also directed to an obvious variant (a disclosed use) of the polypeptide complex of SEQ ID NO: 1 and SEQ ID NO: 2.
Claims 1, 4, 8, 10, 15, 19-21, 24, 28, 38-42, 44, 46, 50-51, and 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31 and 61 of copending Application No. 18055932 (reference application) as evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217 published 28 July 2013. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of '932 make obvious the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 1, 10, and 15, claims 31 and 61 of the ‘932 application teach a method of treating prostate cancer in a subject comprising administering a polypeptide complex according to Formula I: A2-A1-L1-P1-H1 wherein A1 comprises a first antigen recognizing molecule that binds to an effector cell antigen, wherein A1 comprises an anti-CD3 binding molecule comprising complementary determining regions (CDRs) heavy and light chain SEQ ID NOs: 1-6; P1 comprises a peptide that binds to A1 of a particular formula as recited; wherein L1 comprises a linking moiety that connects A1 to P1 and is a substrate for a tumor specific protease; H1 comprises a half-life extending molecule; and A2 comprises a second antigen recognizing molecule that binds to PSMA (claim 31), wherein the polypeptide complex comprises the amino acid sequences according to SEQ ID NO: 72 and SEQ ID NO: 73 which are identical to instant SEQ ID NO: 1 and 2 (claim 61) as shown below:
Query Match 100.0%; Score 3414; Length 645;
Best Local Similarity 100.0%;
Matches 645; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGSTFYTAVMGWVRQAPGKGLEWVAAIRWTALTTSY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGSTFYTAVMGWVRQAPGKGLEWVAAIRWTALTTSY 60
Qy 61 ADSVKGRFTISRDGAKTTLYLQMNSLRPEDTAVYYCAARGTLGLFTTADSYDYWGQGTLV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDGAKTTLYLQMNSLRPEDTAVYYCAARGTLGLFTTADSYDYWGQGTLV 120
Qy 121 TVSSGGGGSGGGSGGVYCGPEFDESVGCMGGGGSGGGLSGRSDAGSPLGLAGSGGGSEVQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TVSSGGGGSGGGSGGVYCGPEFDESVGCMGGGGSGGGLSGRSDAGSPLGLAGSGGGSEVQ 180
Qy 181 LVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYA 240
Qy 241 DSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 DSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTV 300
Qy 301 SSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 SSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPG 360
Qy 361 QAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 QAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGG 420
Qy 421 TKLTVLGGGGSDIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKTGKVPKFLIY 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 TKLTVLGGGGSDIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKTGKVPKFLIY 480
Qy 481 EASTLQSGVPSRFSGGGSGTDFTLTISSLQPEDVATYYCQNYNSAPFTFGPGTKVDIKRT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 EASTLQSGVPSRFSGGGSGTDFTLTISSLQPEDVATYYCQNYNSAPFTFGPGTKVDIKRT 540
Qy 541 VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK 600
Qy 601 DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 645
|||||||||||||||||||||||||||||||||||||||||||||
Db 601 DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 645
Query Match 100.0%; Score 1199; Length 226;
Best Local Similarity 100.0%;
Matches 226; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGVVQPGRSLRLSCAASGFAFSRYGMHWVRQAPGKGLEWVAVIWYDGSNKYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGGGVVQPGRSLRLSCAASGFAFSRYGMHWVRQAPGKGLEWVAVIWYDGSNKYY 60
Qy 61 ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCARGGDFLYYYYYGMDVWGQGTTVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCARGGDFLYYYYYGMDVWGQGTTVT 120
Qy 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
Qy 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 226
||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 226
The claims of ‘932 do not explicitly teach the characteristics:(a) at least one disulfide bond formed by a pair of cysteine residues in the first chain or the second chain or by a pair of cysteine residues in the first chain and the second chain; (b) a secondary structure composition comprising a P-sheet or a random coil; (c) at least one pyroglutamine in the second chain; (d) a melting temperature (Tm) between of about 65 °C to about 85 °C when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0 mg/mL in a buffer comprising 10 mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3 (e) a far UV circular dichroism peak at a wavelength between 190 nm and 205 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.1mg/mL in 10mM potassium phosphate buffer pH 7.0; (f) a far UV circular dichroism dip at a wavelength between 210 nm and 220 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.1mg/mL in 10mM potassium phosphate buffer pH 7.0; or (g) a near UV circular dichroism peak at a wavelength between 250 nm and 300 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0mg/mL in a buffer comprising 10mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3, the claims of the ‘932 patent are silent. However, each of the properties a)-g) are inherent properties of the polypeptide complex consisting of SEQ ID NO: 1 and 2, because a protein with the same primary structure would be expected to have the same secondary structure, tertiary structure, and post-translational modifications provided it is made in a mammalian cell type. In order to determine the meaning of the claims to polypeptide SEQ ID NO: 1 and 2, the specification was consulted (MPEP §804.B.1). The specification discloses that the polypeptide may be made by expression in a host-expression vector system, and that the host may be for example a microorganism or a mammalian cell selected from a list ([199], [217-218]).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make the polypeptide complex using a mammalian host-expression vector system to benefit from a method of making the claimed polypeptide. As set forth in MPEP §2145 (II) “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”. Products of identical composition cannot have mutually exclusive properties. See MPEP § 2112. As evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217 ““the advanced mammalian folding, secretion and post-translational apparatus is capable of producing antibodies indistinguishable from those in the human body with least concerns for immunogenic modifications” (p. 5 right column, “Mammalian Cells” section ¶1, emphasis is the Examiner’s). Thus, a polypeptide complex of SEQ ID NO: 1 and SEQ ID NO: 2 with the characteristics a)-g) as claimed is made obvious by the claims of ‘932 because the polypeptide complex comprising SEQ ID NO: 1 and SEQ ID NO: 2 of ‘932 would inherently possess all of the recited characteristics when made in a mammalian host-expression vector system.
Regarding dependent claims 4, 8, 19, 20, 21, 24, 28, 38-42, 44, 46,and 50-51, as described for claim 1, each of these characteristics would be an inherent property of the polypeptide complex consisting of 100% identity to SEQ ID NO: 1 and SEQ ID NO: 2 provided the polypeptide complex was produced in mammalian cells in order to produce the same folding and post-translational modifications. Thus, the claims directed at the particular disulfide bonds and positions of disulfide bonds (claims 19, 20, 21, 24, 28, 39-41) or lack thereof as free sulfhydryl (claim 38), the secondary and tertiary structures and resultant far UV and near UV circular dichroism peaks (claim 42, 46, 50-51), and melting temperatures would be characteristics inherently possessed by a polypeptide complex that has the same folding and post-translational modifications as the instantly claimed polypeptide complex.
Claims 1, 4, 8, 10, 15, 19-21, 24, 28, 38-42, 44, 46, 50-51, and 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19320207 (reference application) as evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217 published 28 July 2013. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of '207 make obvious the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 1, 10, and 15, claims 1-20 of the ‘207 application teach a method of extending half-life and improving toxicity of a T-cell engager comprising tethering an inhibitory peptide mask to the T-cell engager via a cleavable linker to generate modified T-cell engager according to Formula I: A2-A1-L1-P1-H1 wherein A1 comprises a first antigen recognizing molecule that binds to an effector cell antigen; P1 comprises a peptide that binds to A1 of a particular formula as recited; wherein L1 comprises a linking moiety that connects A1 to P1 and is a substrate for a tumor specific protease; H1 comprises a half-life extending molecule; and A2 comprises a second antigen recognizing molecule(claim 1). Claim 2 recites wherein A1 comprises an antibody selected from a group of formats including single chain variable format; claim 3 recites wherein the A1 is anti-CD3. Claim 4 recites wherein P1 is bound to A1 through a list of types of interactions. Claim 5 recites wherein P1 has less than 70% sequence homology to the effector cell antigen. Claims 6 and 7 recites wherein P1 comprises an amino acid of no more than 40 amin acids, and at least 10 amino acids and no more than 20 amino acids in length. Claims 8-10 recites wherein the tumor specific protease is selected from a group including particular MMPs and serine proteases. Claims 12 and 13 recite the sequence formula for the linker. Claim 17 recites where H1 is a single domain antibody. Claim 19 recites the A2 is selected from a group of antibody formats including a Fab. Claim 20 recites the second antigen recognizing molecule binds to PSMA. In order to understand the scope of the claims, the specification was consulted for embodiments of the particular protein complexes as claimed. The specification recites the polypeptide complexes with pairs of sequences from SEQ ID NOs: 72 and 73, SEQ ID NOs: 62 and 63, SEQ ID NOs: 64 and 65, SEQ ID NOs: 66 and 67, SEQ ID NOs: 68 and 69, SEQ ID NOs: 70 and 71, and SEQ ID NOs: 74 and 75 ([003], see bottom of p. 5- top p. 6) wherein the polypeptide complex comprises the amino acid sequences according to SEQ ID NO: 72 and SEQ ID NO: 73 which are identical to instant SEQ ID NO: 1 and 2 (claim 61) as shown below:
Query Match 100.0%; Score 3414; Length 645;
Best Local Similarity 100.0%;
Matches 645; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGSTFYTAVMGWVRQAPGKGLEWVAAIRWTALTTSY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGSTFYTAVMGWVRQAPGKGLEWVAAIRWTALTTSY 60
Qy 61 ADSVKGRFTISRDGAKTTLYLQMNSLRPEDTAVYYCAARGTLGLFTTADSYDYWGQGTLV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDGAKTTLYLQMNSLRPEDTAVYYCAARGTLGLFTTADSYDYWGQGTLV 120
Qy 121 TVSSGGGGSGGGSGGVYCGPEFDESVGCMGGGGSGGGLSGRSDAGSPLGLAGSGGGSEVQ 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TVSSGGGGSGGGSGGVYCGPEFDESVGCMGGGGSGGGLSGRSDAGSPLGLAGSGGGSEVQ 180
Qy 181 LVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYA 240
Qy 241 DSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 DSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTV 300
Qy 301 SSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPG 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 SSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPG 360
Qy 361 QAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 QAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGG 420
Qy 421 TKLTVLGGGGSDIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKTGKVPKFLIY 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 TKLTVLGGGGSDIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKTGKVPKFLIY 480
Qy 481 EASTLQSGVPSRFSGGGSGTDFTLTISSLQPEDVATYYCQNYNSAPFTFGPGTKVDIKRT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 EASTLQSGVPSRFSGGGSGTDFTLTISSLQPEDVATYYCQNYNSAPFTFGPGTKVDIKRT 540
Qy 541 VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK 600
Qy 601 DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 645
|||||||||||||||||||||||||||||||||||||||||||||
Db 601 DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 645
Query Match 100.0%; Score 1199; Length 226;
Best Local Similarity 100.0%;
Matches 226; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGVVQPGRSLRLSCAASGFAFSRYGMHWVRQAPGKGLEWVAVIWYDGSNKYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVESGGGVVQPGRSLRLSCAASGFAFSRYGMHWVRQAPGKGLEWVAVIWYDGSNKYY 60
Qy 61 ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCARGGDFLYYYYYGMDVWGQGTTVT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCARGGDFLYYYYYGMDVWGQGTTVT 120
Qy 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL 180
Qy 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 226
||||||||||||||||||||||||||||||||||||||||||||||
Db 181 QSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC 226
Thus, the claims of ‘207 are directed towards a genus of which SEQ ID NO: 72 and 73 are obvious species.
The claims of ‘207 do not explicitly teach the characteristics:(a) at least one disulfide bond formed by a pair of cysteine residues in the first chain or the second chain or by a pair of cysteine residues in the first chain and the second chain; (b) a secondary structure composition comprising a P-sheet or a random coil; (c) at least one pyroglutamine in the second chain; (d) a melting temperature (Tm) between of about 65 °C to about 85 °C when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0 mg/mL in a buffer comprising 10 mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3 (e) a far UV circular dichroism peak at a wavelength between 190 nm and 205 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.1mg/mL in 10mM potassium phosphate buffer pH 7.0; (f) a far UV circular dichroism dip at a wavelength between 210 nm and 220 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.1mg/mL in 10mM potassium phosphate buffer pH 7.0; or (g) a near UV circular dichroism peak at a wavelength between 250 nm and 300 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0mg/mL in a buffer comprising 10mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3, the claims of the ‘207 application are silent. However, each of the properties a)-g) are inherent properties of the polypeptide complex consisting of SEQ ID NO: 1 and 2, because a protein with the same primary structure would be expected to have the same secondary structure, tertiary structure, and post-translational modifications provided it is made in a mammalian cell type. In order to determine the meaning of the claims to polypeptide SEQ ID NO: 1 and 2, the specification was consulted (MPEP §804.B.1). The specification discloses that the polypeptide may be made by expression in a host-expression vector system, and that the host may be for example a microorganism or a mammalian cell selected from a list ([194], [217-218]).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make the polypeptide complex using a mammalian host-expression vector system to benefit from a method of making the claimed polypeptide. As set forth in MPEP §2145 (II) “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”. Products of identical composition cannot have mutually exclusive properties. See MPEP § 2112. As evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217 ““the advanced mammalian folding, secretion and post-translational apparatus is capable of producing antibodies indistinguishable from those in the human body with least concerns for immunogenic modifications” (p. 5 right column, “Mammalian Cells” section ¶1, emphasis is the Examiner’s). Thus, a polypeptide complex of SEQ ID NO: 1 and SEQ ID NO: 2 with the characteristics a)-g) as claimed is made obvious by the claims of ‘207 because the polypeptide complex comprising SEQ ID NO: 1 and SEQ ID NO: 2 of ‘207 would inherently possess all of the recited characteristics when made in a mammalian host-expression vector system.
Regarding dependent claims 4, 8, 19, 20, 21, 24, 28, 38-42, 44, 46,and 50-51, as described for claim 1, each of these characteristics would be an inherent property of the polypeptide complex consisting of 100% identity to SEQ ID NO: 1 and SEQ ID NO: 2 provided the polypeptide complex was produced in mammalian cells in order to produce the same folding and post-translational modifications. Thus, the claims directed at the particular disulfide bonds and positions of disulfide bonds (claims 19, 20, 21, 24, 28, 39-41) or lack thereof as free sulfhydryl (claim 38), the secondary and tertiary structures and resultant far UV and near UV circular dichroism peaks (claim 42, 46, 50-51), and melting temperatures would be characteristics inherently possessed by a polypeptide complex that has the same folding and post-translational modifications as the instantly claimed polypeptide complex.
Claims 1, 4, 8, 10, 15, 19-21, 24, 28, 38-42, 44, 46, 50-51, and 53 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11, 55, 136-145, and 150 of copending Application No. 19374607 (reference application) as evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217 published 28 July 2013. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of '607 make obvious the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 1, 10, and 15, claims 11, 55, 136-145, and 150 of the ‘607 application teach an isolated polypeptide according to Formula I: A1-L1-P1 wherein A1 comprises a first antigen recognizing molecule that binds to CD3 comprising particular CDR sequences; P1 comprises a peptide that binds to A1 of SEQ ID NOs: 150-165; wherein L1 comprises a linking moiety that connects A1 to P1 and is a substrate for a tumor specific protease (claim 11). Claim 55 recites wherein the recombinant antibody or antigen binding fragment thereof further comprises an antigen binding domain. Claim 136 recites the antigen binding domain is a PSMA binding domain. Claims 137-145 recite wherein the isolated polypeptide sequence at least 90% identity to particular amino acid sequences that are at least 80% identical to instant SEQ ID NO: 1 and 2 (SEQ ID NOs: 230, 234, 232, 228; and SEQ ID NOs: 231, 235, 229, 233), for example claim 143 wherein the polypeptide complex comprises the amino acid sequences according to SEQ ID NO: 230 and SEQ ID NO: 231 which are 99.6 and 100% identical to instant SEQ ID NO: 1 and 2, respectively.
The claims of ‘607 do not explicitly teach the characteristics:(a) at least one disulfide bond formed by a pair of cysteine residues in the first chain or the second chain or by a pair of cysteine residues in the first chain and the second chain; (b) a secondary structure composition comprising a P-sheet or a random coil; (c) at least one pyroglutamine in the second chain; (d) a melting temperature (Tm) between of about 65 °C to about 85 °C when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0 mg/mL in a buffer comprising 10 mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3 (e) a far UV circular dichroism peak at a wavelength between 190 nm and 205 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.1mg/mL in 10mM potassium phosphate buffer pH 7.0; (f) a far UV circular dichroism dip at a wavelength between 210 nm and 220 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 0.1mg/mL in 10mM potassium phosphate buffer pH 7.0; or (g) a near UV circular dichroism peak at a wavelength between 250 nm and 300 nm when the isolated recombinant polypeptide complex is formulated at a concentration of 1.0mg/mL in a buffer comprising 10mM histidine buffer, 8% (w/v) Sucrose, 0.01% (w/v) polysorbate 20, pH 6.3, the claims of the ‘607 patent are silent. However, each of the properties a)-g) are inherent properties of the polypeptide complex consisting of SEQ ID NO: 1 and 2, because a protein with the same primary structure would be expected to have the same secondary structure, tertiary structure, and post-translational modifications provided it is made in a mammalian cell type. In order to determine the meaning of the claims to polypeptide SEQ ID NO: 1 and 2, the specification was consulted (MPEP §804.B.1). The specification discloses that the polypeptide may be made by expression in a host-expression vector system, and that the host may be for example a microorganism or a mammalian cell selected from a list ([194], [217-218]).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to make the polypeptide complex using a mammalian host-expression vector system to benefit from a method of making the claimed polypeptide. As set forth in MPEP §2145 (II) “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention”. Products of identical composition cannot have mutually exclusive properties. See MPEP § 2112. As evidenced by Frenzel, André, et. al. "Expression of recombinant antibodies." Frontiers in immunology 4 (2013): 217 ““the advanced mammalian folding, secretion and post-translational apparatus is capable of producing antibodies indistinguishable from those in the human body with least concerns for immunogenic modifications” (p. 5 right column, “Mammalian Cells” section ¶1, emphasis is the Examiner’s). Thus, a polypeptide complex of SEQ ID NO: 1 and SEQ ID NO: 2 with the characteristics a)-g) as claimed is made obvious by the claims of ‘607 because the polypeptide complex comprising SEQ ID NO: 1 and SEQ ID NO: 2 of ‘607 would inherently possess all of the recited characteristics when made in a mammalian host-expression vector system.
Regarding dependent claims 4, 8, 19, 20, 21, 24, 28, 38-42, 44, 46,and 50-51, as described for claim 1, each of these characteristics would be an inherent property of the polypeptide complex consisting of 100% identity to SEQ ID NO: 1 and SEQ ID NO: 2 provided the polypeptide complex was produced in mammalian cells in order to produce the same folding and post-translational modifications. Thus, the claims directed at the particular disulfide bonds and positions of disulfide bonds (claims 19, 20, 21, 24, 28, 39-41) or lack thereof as free sulfhydryl (claim 38), the secondary and tertiary structures and resultant far UV and near UV circular dichroism peaks (claim 42, 46, 50-51), and melting temperatures would be characteristics inherently possessed by a polypeptide complex that has the same folding and post-translational modifications as the instantly claimed polypeptide complex.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678