Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-14, and 16-18 are pending and under consideration.
Priority
It is acknowledged that this application is a National Stage of International Application No. PCT/EP2021/076052 filed September 22, 2021, which claims the benefit of priority from EP 20197975.4 filed September 24, 2020. Certified copies of foreign priority applications have been received as required by 37 CFR 1.55.
The priority date has been established as September 24, 2020.
Information Disclosure Statement
The Information Disclosure Statement filed on 04/21/2023 has been considered and entered by examiner.
Claim Rejections - 35 USC § 112
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 6 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 6 recites the limitation "wherein the variable heavy chain and variable light chain" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112
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 1-14 and 16-18 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. This is a WRITTEN DESCRIPTION rejection.
Claim 1 is drawn to “an isolated human antibody or antibody fragment specific for human CD3 epsilon, wherein said antibody or antibody fragment comprises: a) an HCDR1 region comprising the amino acid sequence of GFTFXSX2X3MX4, wherein X1 is S, K or R; X2 is Y or H; X3 is W or Y; and X4 is S or T (SEQ ID NO: 90); b) an HCDR2 region comprising the amino acid sequence of NIX1X2X3X4X5X6X7YYX8X9SVKG, wherein X1 is K or D; X2 is Q or Y; X3 is D, Q or E; X4 is S or G; X5 is S, Q or T; X6 is E, H or R; X7 is K, A or T; X8 is V or A; and X9 is D or E (SEQ ID NO: 91); c) an HCDR3 region comprising the amino acid sequence of GYSAEFAHRSGLDV (SEQ ID NO: 39); d) a LCDR1 region comprising the amino acid sequence of SGSSSNIGX1X2YVY, wherein X1 is S, I, A, K or Q; and X2 is N or T (SEQ ID NO: 92); e) a LCDR2 region comprising the amino acid sequence of RNX1X2RPS, wherein X1 is N, K, S, H, T or Y ; and X2 is Q, I or K (SEQ ID NO: 93); and f) a LCDR3 region comprising the amino acid sequence of AX1WDX2X3X4X5GAV, wherein X1 is A or G; X2 is H or R; X3 is H or R; X4 is R, S or L; and X5 is S or H (SEQ 1D NO: 94)”. The claim encompasses a large number of different CDRs, for example, considering all possible variants, claim 1(b) encompasses 2592 different LCDR2 sequences. Given Broadest Reasonable Interpretation (BRI), the claim encompasses a broad genus of antibody or antibody fragments covering more than 500 million different HCDR: 1-3 and LCDRs: 1-3 combinations. The specification discloses a few antibodies (e.g. MAB-1, MAB-1-25, MAB-1-3, MAB7- MAB27, see Tables 2, 3, 10, 15 and 16) which bind to human CD3 epsilon. No other antibodies or antibody fragments specific to human CD3 epsilon have been disclosed. Thus, these claims lack written description because the specification lacks a representative number of species that satisfies the entirety of the genus.
MPEP 2163 II A 3(a) states: Disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties).
By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract). Wong (Wong et al., MABS, 2021, Vol. 13, No. 1, e1873478, Publication Year: 2021) teaches that sequence-distant antibodies can target the same epitope (Abstract). Thus, one ordinary skill in the art would not be able to visualize other antibodies encompassed by the claims, which binds to a specific antigen (such as CD3 epsilon), based on only the antibodies disclosed in the specification.
In the instant case, the specification discloses a few antibodies (e.g. MAB-1, MAB-1-25, MAB-1-3, MAB7- MAB27, see Tables 2, 3, 10, 15 and 16) which bind to human CD3 epsilon. However, the disclosed antibodies would not tell the structure of other antibodies, variants or antibody fragments encompassed by the claims.
In addition, the claims identify the antibodies by function only, where the function is to:
Cross-reactively binds to cynomolgus CD3 epsilon (claim 7);
Treating or delaying the progression of a cell proliferative disease (claims 17 and 18).
The specification and prior art have not established the relationship between the claimed functions and the structure of the antibody. One of ordinary skilled in the art would not be able to readily recognize/visualize an antibody with required properties. Taken together, applicant has not provided sufficient evidence to show that the inventors possess a genus of antibodies or antibody fragments specific to a human CD3 epsilon which have the claimed properties as claimed.
Although Applicants may argue that it is possible to screen for antibodies with claimed properties/functions, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. "As we held in Lilly, "[a]n adequate written description of a DNA ... 'requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention." 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171 ). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions." Knowledge of screening methods provides no information about the structure of any future antibodies or antibody fragments yet to be discovered that may function as claimed.
Claim 2 recites sequences for HCDR1 (3 sequences), HCDR2 (3 sequences), HCDR3 (1 sequence), LCDR1 (5 sequences), LCDR2 (9 sequences), LCDR3 (3 sequences). Thus, claim 2 encompasses more than thousand different CDR combinations (3*3*5*9*3= 1215). As set forth above, the specification does not provide written description for the broadly claimed CDR combinations.
Claim 3 and 4 recite heavy chain or light chain sequences. Thus, the claims encompass the recited heavy chain or light chain in combination with CDRs recited in claim 1. As set forth above, the specification does not provide support for all the combinations encompassed by these claims.
Claims 5 and 6 recite combinations of variable heavy chain and variable light chains which are not supported by the specification. As set forth above, the specification provides support for antibodies described in Tables 2, 3, 10, 15 and 16, e.g. MAB-1, MAB-1-25, MAB-1-3, MAB7- MAB27, not all combinations of recited VH and VL encompassed by these claims.
Claim 7-14, and 16-18 encompass the broad genus of antibody or antibody fragment of claim 1. Thus, these claims lack written description support as set forth above.
In addition, claims 12, 13, 15 also encompass antibody specifically binds to a cancer associated antigen. Given BRI, these claims would encompass a broad genus antibodies (known or yet to be discovered) binds to a broad genus of cancer associated antigens (known and yet to be discovered). The specification discloses only bispecific antibody (anti-HER2/CD3), see Example 3. Thus, the specification does not provide support for the broadly claimed antibodies which specifically bind to a cancer associated antigen.
Furthermore, claims 17 and 18 are drawn to a method of treating or delaying the progression of a cell proliferative disease in a subject. Thus, these claims further encompass a broad genus of cell proliferative diseases. As evidenced by paragraph [0128] of the instant publication US 2023/0357398 A1, “a cell proliferative disease” would encompass at least all cancers and tumors. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. However, the specification only shows in an in vitro cell assay that co-cultivation of T-cells with a combination of CyCAT polypeptides (a bispecific antibody) with specificity for HER-2 and CD3 inducing killing of HER-2 positive SW-480 colon cancer cells (Example 11, [0905], Table 15). The specification does not disclose results by administering the claimed other claimed antibody or multispecific antibody in a subject, or treating other cell proliferative diseases.
Given the lack of representative species to support the full scope of the claimed inventions, and lack of reasonable structure-function correlation with regards antibody variants that provide claimed activity/function, the present claims lack adequate written description.
Claim 17 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an ENABLEMENT rejection.
Claim 17 is drawn a method of treating or delaying the progression of a cell proliferative disease in a subject in need thereof, said method comprising administering the isolated human antibody or antibody fragment specific for human CD3 epsilon according to claim 1 to the subject (claim 17). As set forth in the rejection above, these claims encompass a broad genus of anti-CD3 antibody or antibody fragment and a broad genus of cell proliferative disease including all cancers and tumors.
To be enabling, 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 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention 5) the state of the art, 6) the relative skill of those in the art, 7) the predictability of the art and 8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Nature of invention and breadth of the claims:
The claim is drawn to a method for treating a broad genus tumors or tumors with various origins with a broad genus of antibodies or antibody fragments. Claim 17, which depends on claim 1, encompasses more than 500 million CDR combinations for CD3 antibody.
Level of unpredictability in the art and State of the prior art:
As evidenced by paragraph [0128] of the instant publication US 2023/0357398 A1, “a cell proliferative disease” would encompass at least all cancers and tumors. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. In addition, the cancer therapy art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity.
The state of the prior art is such that it involves screening both in vitro and in vivo a large number of antibodies to determine which antibody exhibits the desired therapeutic activities, because even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Ni (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024). Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract). Wong (Wong et al., MABS, 2021, Vol. 13, No. 1, e1873478, Publication Year: 2021) teaches that sequence-distant antibodies can target the same epitope (Abstract). As such, the mere generalized description of antibodies that bind a well-characterized antigen (i.e. CD3 epsilon) cannot always suffice to describe adequately antibodies that have an inhibitory or therapeutic effect in the absence of in vivo working example, because the skilled artisan could not immediately predict, recognize, or distinguish those antibodies that bind an antigen with desired therapeutic effect from antibodies that bind the antigen but lack desired therapeutic effect. Thus, one ordinary skill in the art would not be able to visualize other antibodies encompassed by the claims, which binds to a specific antigen (such as CD3 epsilon), based on only the antibodies disclosed in the specification.
In addition, Gerdes et al. (Front. Oncol. 12/18/2014 doi: 10.3389/fonc.2014.00366, pp. 1-12) teach that cancer is a multifaceted disease characterized by heterogeneous genetic alterations, cellular metabolism at the organ, tissue, and cellular levels and these conditions vary between cancers. See abstract and Fig. 1. Gerdes et al. teach that the tumor microenvironment is a highly heterogeneous mix of cellular and non-cellular components and can promote or be antagonistic to tumor growth. See Tumor Microenvironment-Heterogeneity and Anticancer Therapeutic Target-pp. 5-6 and Fig. 1. Thus, different cancers may need to be treated differently.
Direction or guidance and working examples:
MPEP § 608.01 (p) provided that within the specification, "specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. However, in view of the above, the specification only shows in an in vitro cell assay that co-cultivation of T-cells with a combination of CyCAT polypeptides (a multispecific antibody) with specificity for HER-2 and CD3 (including CyCAT-7, CyCAT-8, CyCAT-9, CyCAT-10, CyCAT-11, CyCAT-12, CyCAT-13, CyCAT-14, CyCAT-15, CyCAT-16, CyCAT-17, CyCAT-18, CyCAT-19, CyCAT-20, CyCAT-21, CyCAT-22, CyCAT-23, CyCAT-24, CyCAT-25, CyCAT-26, CyCAT-27) inducing killing of HER-2 positive SW-480 colon cancer cells (Example 11, [0905], Table 15). The specification does not disclose any results by administering an isolated antibody or antibody fragment specific for human CD3 epsilon in a subject for treating any cell proliferative diseases.
The quantity of experimentation needed:
The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the MPEP 2164.01 (a): "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genetech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable."
Applicant is reminded that MPEP 2164.03 teaches “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, 428 F.2d 833, 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 state 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 for it to be enabling. Given only lack of guidance in the specification and prior art, no one skilled in the art would accept the assertion that the claimed invention would function as contemplated or as claimed based only on the information in the specification and prior art and that known in the art at the time the invention was made.
The specification and prior art provide insufficient guidance with regard to these issues and provides insufficient working examples which would provide guidance to one skilled in the art and no evidence has been provided which would allow one of skill in the art to predict that the invention will function as contemplated or claimed with a reasonable expectation of success. For the above reasons, it appears that undue experimentation would be required to practice the claimed invention.
Due to the large quantity of experimentation necessary to test the use the broadly claimed antibodies or multispecific antibodies for all the cell proliferative diseases (including all cancers and tumors) by the claims; the lack of direction/guidance presented in the specification regarding to treating cell proliferative diseases; the state of the prior art which establishes the unpredictability cancer treatment in general and treatment of cancers; and the breadth of the claims, undue experimentation would be required of the skilled artisan to use the claimed invention in its full scope.
Claim 18 is 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 method of treating or delaying the progression of a cell proliferative disease in a subject in need thereof, said method comprising administering the multispecific antibody according to claim 12 to the subject, wherein the multispecific antibody is a CyCAT-7, CyCAT-8, CyCAT-9, CyCAT-10, CyCAT-11, CyCAT-12, CyCAT-13, CyCAT-14, CyCAT-15, CyCAT-16, CyCAT-17, CyCAT-18, CyCAT-19, CyCAT-20, CyCAT-21, CyCAT-22, CyCAT-23, CyCAT-24, CyCAT-25, CyCAT-26, CyCAT-27, and wherein the cell proliferative disease is a HER2 expressing colon cancer”
does not reasonably provide enablement for
“a method of treating or delaying the progression of a cell proliferative disease in a subject in need thereof, said method comprising administering the multispecific antibody according to claim 12 to the subject”.
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/or use the invention commensurate in scope with these claims. This is a SCOPE of ENABLEMENT rejection.
Claim 18 is drawn a method of treating or delaying the progression of a cell proliferative disease in a subject in need thereof, said method comprising administering the multispecific antibody according to claim 12 to the subject. As set forth in the rejection above, these claims encompass a broad genus of multispecific antibody or antibody fragments and a broad genus of cell proliferative disease including all cancers and tumors.
To be enabling, 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 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are:
1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention 5) the state of the art, 6) the relative skill of those in the art, 7) the predictability of the art and 8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108,427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
Nature of invention and breadth of the claims:
The claim is drawn to a method for treating a broad genus tumors or tumors with various origins with a broad genus of antibodies or antibody fragments. Claim 18, which depends on claim 12, encompasses more than 500 million CDR combinations for CD3 antibody and further encompass antibodies to a broad genus of cancer associated antigens.
Level of unpredictability in the art and State of the prior art:
As evidenced by paragraph [0128] of the instant publication US 2023/0357398 A1, “a cell proliferative disease” would encompass at least all cancers and tumors. Cancer is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. In addition, the cancer therapy art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity.
The state of the prior art is such that it involves screening both in vitro and in vivo a large number of antibodies to determine which antibody exhibits the desired therapeutic activities, because even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Ni (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024). Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract). Wong (Wong et al., MABS, 2021, Vol. 13, No. 1, e1873478, Publication Year: 2021) teaches that sequence-distant antibodies can target the same epitope (Abstract). As such, the mere generalized description of antibodies that bind a well-characterized antigen (i.e. CD3 epsilon) cannot always suffice to describe adequately antibodies that have an inhibitory or therapeutic effect in the absence of in vivo working example, because the skilled artisan could not immediately predict, recognize, or distinguish those antibodies that bind an antigen with desired therapeutic effect from antibodies that bind the antigen but lack desired therapeutic effect. Thus, one ordinary skill in the art would not be able to visualize other antibodies encompassed by the claims, which binds to a specific antigen (such as CD3 epsilon), based on only the antibodies disclosed in the specification.
In addition, Gerdes et al. (Front. Oncol. 12/18/2014 doi: 10.3389/fonc.2014.00366, pp. 1-12) teach that cancer is a multifaceted disease characterized by heterogeneous genetic alterations, cellular metabolism at the organ, tissue, and cellular levels and these conditions vary between cancers. See abstract and Fig. 1. Gerdes et al. teach that the tumor microenvironment is a highly heterogeneous mix of cellular and non-cellular components and can promote or be antagonistic to tumor growth. See Tumor Microenvironment-Heterogeneity and Anticancer Therapeutic Target-pp. 5-6 and Fig. 1. Thus, different cancers may need to be treated differently.
In addition, in the instant application, the activity of CyCAT is based on that the Fab of HER-2 binding domain bring CD3 specific VH and VL domains (see [0906] of the instant publication US 2023/0357398 A1: [0906] These results clearly demonstrate that the CD3 specific VH and VL domains comprised in each of the unpaired CyCAT polypeptides are complemented to a functional CD3 specific antibody Fv domain once both CyCAT polypeptides are bound via their Fab portion to the target antigen on the cancer cell and the two polypeptides get in close proximity. Accordingly, the newly identified CD3 specific human antibodies according to the present disclosure can be used in various approaches to efficiently re-direct T-cells to kill tumor expressing cells). Thus, the expression level of HER2 would determine the density of HER-2 protein on the surface of the cancer cells which would impact the activity of the CyCAT antibodies.
Direction or guidance and working examples:
MPEP § 608.01 (p) provided that within the specification, "specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. However, in view of the above, However, the specification only shows in an in vitro cell assay that co-cultivation of T-cells with a combination of CyCAT polypeptides with specificity for HER-2 and CD3 (including CyCAT-7, CyCAT-8, CyCAT-9, CyCAT-10, CyCAT-11, CyCAT-12, CyCAT-13, CyCAT-14, CyCAT-15, CyCAT-16, CyCAT-17, CyCAT-18, CyCAT-19, CyCAT-20, CyCAT-21, CyCAT-22, CyCAT-23, CyCAT-24, CyCAT-25, CyCAT-26, CyCAT-27) inducing killing of HER-2 positive SW-480 colon cancer cells (Example 11, [0905], Table 15). The specification does not disclose any results for other multispecific antibodies for treating any other cell proliferative diseases.
The quantity of experimentation needed:
The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the MPEP 2164.01 (a): "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genetech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable."
Applicant is reminded that MPEP 2164.03 teaches “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, 428 F.2d 833, 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 state 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 for it to be enabling. Given only lack of guidance in the specification and prior art, no one skilled in the art would accept the assertion that the claimed invention would function as contemplated or as claimed based only on the information in the specification and prior art and that known in the art at the time the invention was made.
The specification and prior art provide insufficient guidance with regard to these issues and provides insufficient working examples which would provide guidance to one skilled in the art and no evidence has been provided which would allow one of skill in the art to predict that the invention will function as contemplated or claimed with a reasonable expectation of success. For the above reasons, it appears that undue experimentation would be required to practice the claimed invention.
Due to the large quantity of experimentation necessary to test the use the broadly claimed antibodies or multispecific antibodies for all the cell proliferative diseases (including all cancers and tumors) by the claims; the lack of direction/guidance presented in the specification regarding to treating cell proliferative diseases; the state of the prior art which establishes the unpredictability cancer treatment in general and treatment of cancers; and the breadth of the claims, undue experimentation would be required of the skilled artisan to use the claimed invention in its full scope.
Related Prior Art
Tiefenthaler (Tiefenthaler et al., WO 2015/181098 A1, Publication Date: 12/3/2015, cited in IDS of 04/21/2023) disclosed a (cynomolgus cross-reactive) antibody specially binding to human CD3 epsilon (claim 14). Tiefenthaler teaches that the antibodies can be human antibody. Tiefenthaler teaches methods to identify such human antibodies are disclosed (pages 25-27). Tiefenthaler teaches methods of treating cancer with an anti-CD3 epsilon antibody (page 47, para. 1). Tiefenthaler teaches multispecific antibody comprising the anti-CD3 epsilon antibody (page 28). However, Tiefenthaler does not teach the antibodies with specific sequences recited by the instant application.
Tiller (Tiller et al., WO 2019/034580 A1, Publication Date: 02/21/2019, cited in IDS of 04/21/2023) teaches the humanization of murine anti-CD3 antibody SP34 which cross-reacts with human and cynomolgus CD3 (example 1 ); the humanized variants have nanomolar affinity to human CD3 epsilon (Table 10); bispecific constructs that bind to CD3 and HER2 are constructed with the CD3 binding portion being scFv (example 7); it is also disclosed that antibodies can be human antibodies (page 14 and 53). However, Tiller does not teach the antibodies with specific sequences recited by the instant application.
Ebert (Ebert et al., WO2008/119567, Publication Date: 10/9/2008, cited in IDS of 04/21/2023) teaches a polypeptide comprising a binding domain capable of binding to
an epitope of human and non-chimpanzee primate CD3 epsilon chain (claim 1 ),
wherein said binding domain capable of binding to an epitope of the human and
non-chimpanzee primate CD3 epsilon chain is of human origin (claim 2) wherein
the polypeptide comprises a first binding domain capable of binding to an
epitope of human and non-chimpanzee primate CD3 epsilon chain and a second binding domain capable of binding to a cell surface antigen (claim 3),
wherein the cell surface antigen is a tumor antigen (claim 11) such as Her2/neu
(claim 12). The examples of Ebert exclusively relate to the CD3-specific antibodies. However, Ebert does not teach the antibodies with specific sequences recited by the instant application.
Conclusion
No claims are allowed.
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/CHENG LU/Examiner, Art Unit 1642