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
2. Applicant's election of Group I (claims 1-14) without traverse in the reply filed on July 8, 2026 is acknowledged. Claims 15-17, and 20 are canceled; and claims 1-14 and 18-19 were pending, with claims 18-19 presently withdrawn from further consideration as being drawn to a nonelected invention. Claims 1-14 are therefore subject to examination.
Objection to the Specification
3. The instant specification is objected to for the following reasons:
There are trademarks in this application that do not meet the requirements.
The use of the term (e.g., “GE Healthcare” and “Sigma” at para. [0087]), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
4. 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.
Written Description
5. Claims 1-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that:
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The claims are directed to: an expression system for an antigen binding molecule, wherein the antigen binding molecule is either secretable or membrane-bound, comprising: - a first antigen binding polynucleotide encoding a first part of the antigen binding molecule; - a cleavage polynucleotide encoding a cleavage site comprising a Furin consensus sequence RXKR (SEQ ID NO: 1) or RXRR (SEQ ID NO: 2), and a 2A polypeptide fragment thereof; - an anchor polynucleotide encoding a membrane anchor polypeptide; wherein the 2A polypeptide fragment thereof comprises one or more mutations in any one of the amino acid residue to control the cleavage efficiencies of the cleavage site to modulate ratio of production of the secretable antigen binding molecule versus the membrane- bound antigen binding molecule; wherein the cleavage polynucleotide is in between the first antigen binding polynucleotide and the anchor polynucleotide; wherein when the cleavage site is cleaved, the secretable antigen binding molecule comprising the first part of the antigen binding molecule is released; wherein when the cleavage site is not cleaved, the membrane-bound antigen binding molecule comprising the first part of the antigen binding molecule, the Furin consensus sequence RXKR (SEQ ID NO: 1) or RXRR (SEQ ID NO: 2), the 2A polypeptide fragment thereof, and the membrane anchor polypeptide, is released.
The claimed antigen binding molecule must possess specific functions, including being cleavable to effectuate a ratio of membrane-bound to secreted antigen binding molecule. The claims encompass thousands of 2A polypeptide fragments and also having any one of the 40 Furin consensus sequences instantly claimed. However, the specification only sets forth the 10 constructs of FIG. 7—having specific P2A fragments and the RRKR Furin consensus sequence—as potentially having the required function. These 10 species (and only having the RRKR Furin consensus sequence) are not sufficiently representative of such a broad genus of antigen binding molecule as instantly claimed because: (i) the genus of 40 instantly claimed Furin consensus sequences will be highly variable as to cleavage efficiency; and (ii) it is wholly unpredictable which members of the genus of instantly claimed of 2A polypeptide fragments (thousands) will beneficially control cleavage efficiency. The combination of these two factors results in the claims encompassing thousands of antigen binding molecules with unknown abilities to effectuate the ratio of membrane-bound to secreted antigen binding molecule. Therefore, the 10 specific antigen binding molecules presented in the specification (all having specific P2A sequences and the RRKR Furin consensus sequence) are not sufficiently representative of the genus and antigen binding molecules instantly claimed.
A. No written description for the breath of the claims (“Furin consensus sequence RXKR or RXRR”), written description is only present for the RRKR Furin consensus sequence:
The claimed invention recites that the antigen binding molecule comprises “a cleavage site comprising a Furin consensus sequence RXKR (SEQ ID NO: 1) or RXRR (SEQ ID NO: 2)[.]” The claims therefore encompass antigen binding molecules having a genus of 40 Furin consensus sequences because the wildcard in the two instantly-claimed sequences can by any amino acid. However, the specification only discloses: secretion of constructs having the RRKR Furin consensus sequence at FIGs. 5, 6, and 7. No other Furin consensus sequences are tested by Applicant.
The claimed antigen binding molecule must possess specific functions, including being cleavable to effectuate some beneficial ratio of membrane-bound to secreted antigen binding molecule. However, a definition by function does not suffice to define the genus because it is only an indication of what the antigen binding molecule does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of antigen binding molecules is highly variable (i.e., each would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed antigen binding molecules have no correlation between their structure and function.
The specification only sets forth the Furin consensus sequence of RRKR as potentially having the claimed functionality, however this single species of Furin consensus sequence is not sufficiently representative of the genus of 40 consensus sequences instantly claimed because: the genus of 40 instantly claimed Furin consensus sequences will be highly variable as to cleavage efficiency.
To demonstrate this issue, a brief assessment of the stat of the art regarding Furin consensus sequences is made herein, showing the genus of Furin consensus sequences instantly claimed is highly variable as to cleavage efficiency, and therefore it is unknown how well antigen binding molecules comprising said genus will be cleaved to effectuate beneficial ratios of secreted to membrane-bound antigen binding molecule.
Shiryaev et al. ("High-resolution analysis and functional mapping of cleavage sites and substrate proteins of furin in the human proteome." PloS one 8.1 (2013): e54290.) is a comprehensive analysis of Furin cleavage sites (see the title). Shiryaev et al. shows that peptides vary widely in magnitude of Furin proteolysis, and points to Table S2 where 5867 peptides are identified having Z scores ranging from >10 (highly sensitive to Furin proteolysis) to <3.5 (resistant to Furin proteolysis). Shiryaev et al. at Analysis of Furin Cleavage Preferences. 6 of the first 10 entries in Table S2 have Furin consensus sequences encompassed by instant claims, with various amino acids in the wildcard position. The Z scores ranged from 1.1 (resistant to Furin proteolysis) to 12.5 (highly sensitive to Furin proteolysis). Shiryaev et al. therefore shows that the genus of instantly claimed Furin consensus sequences will be highly variable as to cleavage efficiency.
Neither the art nor the specification provides a sufficient representative number of Furin consensus sequences to meet the written description requirement for instant claims encompassing antigen binding molecules having a genus of 40 Furin consensus sequences and requiring cleavage to effectuate some beneficial ratio of membrane-bound to secreted antigen binding molecule.
It is therefore unknown the encompassed genus of Furin consensus sequences will be cleaved to render secreted and membrane-bound antigen binding molecule. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of antigen binding molecules encompassed by the claims. Given all of the above, Applicant does not have written description for antigen binding molecules comprising Furin consensus sequences other than the Furin consensus sequence: RRKR.
B. No written description for the breath of the claims (“2A polypeptide fragment thereof comprises one or more mutations; and 2A fragment sequences selected from F2A, E2A, and T2A”); written description is only present for the P2A polypeptides of SEQ ID NOs: 51-60:
The claimed invention further recites that: (i) the 2A polypeptide is a 2A polypeptide fragment; (ii) the 2A polypeptide fragment comprises one or more mutation in any one of the amino acid residues to control the cleavage efficiency and modulate the ratio of membrane-bound to secretable antigen binding molecule; (iii) and the 2A polypeptide fragment may be selected from P2A, F2A, E2A, and T2A. The claims therefore encompass thousands of 2A polypeptide fragments.
In contrast, the specification only discloses the use of 10 specific P2A fragments at e.g., FIG. 7. The fragments are all 5 amino acids long (i.e., the first 5 amino acids of full-length of P2A), correspond to instant SEQ ID NOs: 51-60, and have at most 1 mutation relative to the wild-type P2A sequence.
The claims recite functional language of the antigen binding molecule such as controlling the cleavage efficiency, however a definition by function does not suffice to define the genus because it is only an indication of what the antigen binding molecule does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of antigen binding molecules is highly variable (i.e., each antigen binding molecule would necessarily have a unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed antigen binding molecules have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of the consequences of fragmenting proteins or peptides is provided below, which demonstrates the general principle that it is highly unpredictable what biological activity antigen binding molecules having the claim-encompassed fragments and mutants of the 2A polypeptide will have.
Souza‐Silva et al. ("Peptide fragments of bradykinin show unexpected biological activity not mediated by B1 or B2 receptors." British Journal of Pharmacology 179.12 (2022): 3061-3077) teaches regarding fragments of the 9 amino acid Bradykinin sequence: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was unpredictable that fragments of this 9 amino acid sequence would have substantially different biological activity compared to the full-length amino acid sequence.
In contrast, Zablocki et al. ("Potent in vitro and in vivo inhibitors of platelet aggregation based upon the Arg-Gly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor." Journal of medicinal chemistry 36.13 (1993): 1811-1819) teaches regarding a fragment of the 4 amino acid RGDF sequence that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the 4 amino acid sequence showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of a fragmenting a short amino acid sequence resulting in substantially different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting a different short amino acid sequence resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible 2A polypeptide fragments encompassed by the instant claims. Therefore, without performing the required experiments, it is wholly unpredictable which 2A polypeptide fragments will beneficially control cleavage efficiency.
Neither the art nor the specification provides a sufficient representative number of 2A polypeptide fragments to meet the written description requirement for instant claims directed to 2A polypeptide fragment having one or more mutants and selected from P2A, F2A, E2A, and T2A polypeptide.
It is therefore unknown how the genus of 2A polypeptide fragments as instantly claimed will affect the cleavage of the claimed invention. Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genera of 2A polypeptides encompassed by the claims. Given all of the above, Applicant does not have written description for 2A polypeptide fragment having one or more mutants and selected from P2A, F2A, E2A, and T2A polypeptide.
The cited reference therefore demonstrate that Applicant is not in possession of: the genera of 40 Furin consensus sequences and 2A polypeptide fragment having one or more mutants and selected from P2A, F2A, E2A, and T2A polypeptide; Applicant is in possession of: an antigen binding molecule having Furin consensus sequence RRKR paired the specific 5-amino acid long P2A variants demonstrated in FIG. 7 (i.e., SEQ ID NOs: 51-60).
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
6. Claims 1-14 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 the 10 antigen binding molecules exemplified at e.g., FIG 7, does not reasonably provide enablement for broad genus antigen binding molecules instantly claimed, encompassing thousands of additional species. 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.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
3) the state of the prior art;
4) the level of one of ordinary skill;
5) the level of predictability in the art;
6) the amount of direction or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(2) The breadth of the claims:
The claims are drawn to an expression system for an antigen binding molecule with specific cleavability features. The antigen binding molecule comprises “a cleavage site comprising a Furin consensus sequence RXKR (SEQ ID NO: 1) or RXRR (SEQ ID NO: 2),” which encompasses 40 distinct Furin consensus sequences; and 2A polypeptide fragments and mutants.
The claims are therefore broad and encompass thousands of antibody binding molecule structures.
(5) The predictability or unpredictability of the art:
The state of the art indicates it is very unpredictable how well members of the instantly-claimed genus of antigen binding molecules will effectuate cleavage to render a ratio of membrane-bound and secreted antigen binding molecule
It is unpredictable which Furin consensus sequences other than RRKR will work
The specification only discloses results using the RRKR Fusion consensus sequence, yet a genus including 39 additional sequences is instantly claimed. The antigen binding molecule must effectuate some beneficial cleavage ratio. To address this issue, a brief assessment of the state of the art of Furin consensus sequences is presented herein, which demonstrates some of the encompassed Furin consensus sequences will work, and others will not, but it is not predictable which ones will work or not without performing the required experiments.
Shiryaev et al. is a comprehensive analysis of Furin cleavage sites (see the title). Shiryaev et al. shows that peptides vary widely in magnitude of Furin proteolysis, and points to Table S2 where 5867 peptides are identified having Z scores ranging from >10 (highly sensitive to Furin proteolysis) to <3.5 (resistant to Furin proteolysis). Shiryaev et al. at Analysis of Furin Cleavage Preferences. 6 of the first 10 entries in Table S2 have Furin consensus sequences encompassed by instant claims, with various amino acids in the wildcard position. The Z scores ranged from 1.1 (resistant to Furin proteolysis) to 12.5 (highly sensitive to Furin proteolysis). Shiryaev et al. therefore shows that the genus of instantly claimed Furin consensus sequences will be highly variable as to cleavage efficiency.
If is therefore highly unpredictable which of the encompassed Furin consensus sequences will work.
It is unpredictable which 2A polypeptide fragments will work other than the 10 demonstrated in e.g., FIG. 7
The specification only discloses antigen binding molecules having 2A fragments that are 5 amino acid long P2A fragments with single point mutations, yet the claims encompass thousands of additional 2A fragments and mutants. The antigen binding molecule must effectuate some beneficial cleavage ratio. To address this issue, a brief assessment of the state of the art of “fragments” is presented herein, which demonstrates it is unpredictable which of the encompassed 2A polypeptide fragments and mutants will work.
Souza‐Silva et al. teaches regarding fragments of the 9 amino acid Bradykinin sequence: “BK-(1–7) and BK-(1–5) are produced in vivo from BK-(1–9). Both peptides induced NO production in all cell types tested. However, unlike BK-(1–9), NO production elicited by BK-(1–7) or BK-(1–5) was not inhibited by B1 or B2 receptor antagonists.” Souza‐Silva et al. at abstract. Therefore, it was unpredictable that fragments of this 9 amino acid sequence would have substantially different biological activity compared to the full-length amino acid sequence.
In contrast, Zablocki et al. teaches regarding a fragment of the 4 amino acid RGDF sequence that surprisingly: “[p]reviously, we had shown that the inherent inhibitory potency of Arg-Gly-Asp-Phe [RGDF] for disrupting the fibrinogen-GP Ilb-IIIa interaction can be enhanced 15-fold by removing the Arg-NH2 and the Arg-Gly amide bond to obtain 8-guanidinooctanoyl-Asp-Phe[GOA-Asp Phe]” Zablocki et al. at introduction. In other words, the fragment of the 4 amino acid sequence showed a large increase in inhibitory activity compared to the full-length tetrapeptide.
The above juxtaposition of a fragmenting a short amino acid sequence resulting in substantially different biological activity as illustrated by Souza‐Silva et al. compared to fragmenting a different short amino acid sequence resulting in a large increase in (inhibitory) activity illustrated by Zablocki et al. shows it is very unpredictable what effects will be obtained with all the possible 2A polypeptide fragments encompassed by the instant claims. Therefore, without performing the required experiments, it is wholly unpredictable which of the encompassed 2A polypeptide fragments will beneficially control cleavage efficiency.
6) the amount of direction or guidance provided by the inventor:
The specification discloses: 10 specific antigen binding molecules. Given the evidence above, one of skill in the art could not reasonably extrapolate the instant findings regarding the cleavage activity of these 10 antigen binding molecules to the broad genus of antigen binding molecules instantly claimed, which includes thousands of additional species. It would also be undue experimentation to confirm which of the thousands of encompassed antigen binding molecules achieve a beneficial ratio of membrane-binding vs secretion.
8) the quantity of experimentation needed to make or use the invention:
It would be undue experimentation to make or use the invention encompassed by the breadth of the claims because thousands of antigen binding molecules would need to be produced and tested for efficacy; Applicant has only made and evaluated 10.
In conclusion, the claimed invention does not provide enablement for an antigen binding molecule having Furin consensus sequence RXKR or RXRR and 2A polypeptide fragment / mutants; the claimed invention provides enablement for an antigen binding molecule having Furin consensus sequence RRKR and the P2A fragments of SEQ ID NOs: 51-60. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
7. 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.
Claims 1-14 are rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
A. Claims 1 and 8 recite that (i) when the cleavage site is cleaved (i.e., the secreted form of the antigen binding molecule), the first part of the antigen binding molecule is released; and (ii) when the cleavage site is not cleaved (i.e., the membrane bound form of the antigen binding molecule), the entire antigen binding molecule is “released.” The second instance of the term “released” in the claims is unclear since it is referring to the membrane-bound configuration, not the secreted form. If “released” means in the context of the secreted form of the antigen binding molecule—secretion of the molecule—how can the membrane bound form of the antigen binding also be “released” or secreted? What is the membrane bound form of the antigen binding molecule “released” from? Appropriate clarification and/or correction is requested.
B. Claims 1 and 8 recite a “first part of the antigen binding molecule.” Claims 2 and 9 recite a “second part of the antigen binding molecule.” It is unclear if the first part of the antigen binding molecule is part or all of a heavy chain; if the second part of the antigen binding molecule is part or all of a light chain; vice versa; or something else entirely. Appropriate clarification and/or correction is requested.
C. Claims 1 and 9 recite a “cleavage efficiency” to modulate the ratio of secreted to membrane bound antigen binding molecule. The claims do not further specify what the ratio is. It is therefore unclear what efficiencies the term “cleavage efficiency” encompass, rendering the claims unclear. Do the claims include cleavage efficiencies of 0% and 100%? Appropriate clarification and/or correction is requested.
D. Claims 5 and 12 require the 2A polypeptide fragment comprising one or more amino acid mutations to be “mutated to glycine, proline, or alanine.” However, without specifying what the amino acid was, it is unclear how the amino acid may be mutated to glycine, proline, or alanine. Appropriate clarification and/or correction is requested.
Claim Rejections - 35 USC § 102
8. 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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
9. Claims 1-5, 7-12, and 14 are rejected under 35 U.S.C 102 (a)(2) as anticipated by Yu et al. (US 20130316366 A1; published November 28, 2013).
Claim 1 is directed to an expression system for an antigen binding molecule, wherein the antigen binding molecule is either secretable or membrane-bound, comprising: - a first antigen binding polynucleotide encoding a first part of the antigen binding molecule; - a cleavage polynucleotide encoding a cleavage site comprising a Furin consensus sequence RXKR (SEQ ID NO: 1) or RXRR (SEQ ID NO: 2), and a 2A polypeptide fragment thereof; - an anchor polynucleotide encoding a membrane anchor polypeptide; wherein the 2A polypeptide fragment thereof comprises one or more mutations in any one of the amino acid residue to control the cleavage efficiencies of the cleavage site to modulate ratio of production of the secretable antigen binding molecule versus the membrane- bound antigen binding molecule; wherein the cleavage polynucleotide is in between the first antigen binding polynucleotide and the anchor polynucleotide; wherein when the cleavage site is cleaved, the secretable antigen binding molecule comprising the first part of the antigen binding molecule is released; wherein when the cleavage site is not cleaved, the membrane-bound antigen binding molecule comprising the first part of the antigen binding molecule, the Furin consensus sequence RXKR (SEQ ID NO: 1) or RXRR (SEQ ID NO: 2), the 2A polypeptide fragment thereof, and the membrane anchor polypeptide, is released.
Claim 2 is directed to the expression system of claim 1, further comprising a second antigen binding polynucleotide encoding a second part of the antigen binding molecule.
Claim 3 is directed to the expression system of claim 2, wherein the 2A polypeptide fragment thereof comprises one or more mutations in amino acid residue 1, 2, 3, 4, or 5.
Claim 4 is directed to the expression system of claim 1, wherein the 2A polypeptide fragment thereof is selected from a group consisting of a P2A, F2A, E2A, and T2A fragment thereof.
Claim 5 is directed to the expression system of claim 1, wherein the amino acid is mutated to glycine, proline, or alanine.
Claim 7 is directed to the expression system of claim 1, wherein the membrane anchor polypeptide is glycophospholipid transmembrane domain (GPI), platelet-derived growth factor receptor (PDGFR) beta chain transmembrane domain (PTM), or immunoglobulin C2-type extracellular-transmembrane-cytosolic domains of murin B7-1 antigen.
Claim 8 is directed to an expression system for an antigen binding molecule, wherein the antigen binding molecule is either secretable or membrane-bound, comprising: - a first antigen binding polynucleotide encoding a first part of the antigen binding molecule; - a first cleavage polynucleotide encoding a first cleavage site, wherein the first cleavage site is a minimal Furin cleavage consensus sequence RXKR (SEQ ID NO: 1) or RXRR (SEQ ID NO: 2); - a second cleavage polynucleotide encoding a self-processing second cleavage site, wherein the self-processing second cleavage site is a 2A polypeptide or a fragment thereof; - an anchor polynucleotide encoding a membrane anchor polypeptide; wherein the 2A polypeptide or the fragment thereof comprises one or more mutations in any one of the amino acid residue to control the cleavage efficiencies of the first cleavage site and the second cleavage site to modulate ratio of production of the secretable antigen binding molecule versus the membrane-bound antigen binding molecule; wherein the first and second cleavage polynucleotides are in between the first antigen binding polynucleotide and the anchor polynucleotide; wherein when the first cleavage site is cleaved, the secretable antigen binding molecule comprising the first part of the antigen binding molecule is released; wherein when the first and second cleavage sites are not cleaved, the membrane-bound antigen binding molecule comprising the first part of the antigen binding molecule, the minimal Furin cleavage consensus sequence RXKR (SEQ ID NO: 1) or RXRR (SEQ ID NO: 2), the 2A polypeptide or a fragment thereof, and the membrane anchor polypeptide, is released.
Claim 9 is directed to the expression system of claim 8, further comprising a second antigen binding polynucleotide encoding a second part of the antigen binding molecule.
Claim 10 is directed to the expression system of claim 8, wherein the 2A polypeptide or a fragment thereof comprises one or more mutations in amino acid residue 1, 2, 3, 4, or 5.
Claim 11 is directed to the expression system of claim 8, wherein the 2A polypeptide or a fragment thereof is selected from a group consisting of P2A, F2A, E2A and T2A, or a fragment thereof.
Claim 12 is directed to the expression system of claim 8, wherein the amino acid is mutated to glycine, proline, or alanine.
Claim 14 is directed to the expression system of claim 8, wherein the membrane anchor polypeptide is glycophospholipid transmembrane domain (GPI), platelet-derived growth factor receptor (PDGFR) beta chain transmembrane domain (PTM), or immunoglobulin C2-type extracellular-transmembrane-cytosolic domains of murine B7-1 antigen.
Yu et al. is titled “Expression of Secreted and Cell-Surface Polypeptides,” and at FIG. 1A discloses a nucleotide expression construct (i.e., “expression system”) having a secreted IgM heavy chain (i.e., “first part of an antigen binding molecule”) linked via a 2A element to the transmembrane region of the membrane form of the IgM heavy chain (i.e. “anchor polynucleotide encoding a membrane anchor polypeptide”). See also Yu et al. at para. [0127]. FIG. 1A is reproduced below for Applicant’s convenience:
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Yu et al. discloses further comprising “the second part of an antigen binding molecule” (i.e., light chain) at e.g., FIG. 2A, reproduced below for Applicant’s convenience:
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Yu et al. further discloses an “optimized 2A element with a Furin cleavage site at the 5’ end” i.e., optimized for cleavage, at para. [0128]; and the Furin consensus sequences RXKR (i.e., instant SEQ ID NO: 1) and RXRR (i.e., instant SEQ ID NO: 2) at para. [0034]. Said Furin consensus sequences are denoted as the preferred Furin consensus sequences.
Yu et al. also discloses 2A polypeptide mutations / fragments at Table 1 (including F2A having 1st amino acid mutated, and I2A with alanine mutation), which reads on instant claims 3-5 and 10-12, and further encourages selection of the 2A polypeptide based on relative activity (i.e., to “control the cleavage efficiencies of the cleavage site to modulate ratio of production of the secretable antigen binding molecule versus the membrane-bound antigen binding molecule”). Yu et al. at para. [0037]; see also para. [0133] (“the ratio of surface-bound to secreted immunoglobulins by making appropriate mutations in the 2A elements was manipulated”).
Yu et al. also discloses the membrane anchor polypeptide may be an GPI anchor at para. [0041].
Accordingly, Yu et al. anticipates claims 1-5, 7-12, and 14.
Conclusion
10. No claim is allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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