Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Status of the Claims
1. Claims 1-6 are the original claims filed on 8/21/2023. Claims 1-6 are all the claims for this application.
Priority
2. USAN 18/453,107, filed 08/21/2023, is a Continuation of 16/932,588, filed 07/17/2020, now abandoned, 16/932,588 is a Continuation of 15/447,622, filed 03/02/2017, now abandoned and having 1 RCE-type filing therein,
15/447,622 is a Continuation of 14/374,612, filed 07/25/2014, now abandoned and having 1 RCE-type filing therein, 14/374,612 is a National Stage entry of PCT/GB2013/ 050164, International Filing Date: 01/25/2013, claims foreign priority to GB 1201314.0, filed 01/26/2012. Applicants claim to benefit of priority for the claimed method invention as of the filing date 1/26/2012 for foreign priority application GB 1201314.0 is granted.
Information Disclosure Statement
3. As of 3/2/2026, a total of three (3) IDS are filed: 8/21/2023 (7 pages); 8/21/2023 (12 pages); and 8/21/2023 (10 pages). The corresponding initialed and dated 1449 is considered and of record for the IDS filings on 8/21/2023 (7 pages) and 8/21/2023 (10 pages).
4. The information disclosure statement filed 8/21/2023 (12 pages) fails to comply with 37 CFR 1.98(a)(1), which requires the following: (1) a list of all patents, publications, applications, or other information submitted for consideration by the Office; (2) U.S. patents and U.S. patent application publications listed in a section separately from citations of other documents; (3) the application number of the application in which the information disclosure statement is being submitted on each page of the list; (4) a column that provides a blank space next to each document to be considered, for the examiner’s initials; and (5) a heading that clearly indicates that the list is an information disclosure statement. The information disclosure statement has been placed in the application file, but the information referred to therein has not been considered.
Objections
Specification
5. The disclosure is objected to because of the following informalities:
a) The use of the terms GenBank, Tween, Sepharose, GraphPad, Spectramax, Rituxan, Yervoy (misspelled “Yermoy”), 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.
b) Amend the specification to correct the misspelling of “Yervoy” from “Yermoy.”
Appropriate correction is required.
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.
6. Claim 2 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 pre-AIA the applicant regards as the invention.
a) Claim 2 is indefinite for reciting parenthetical text for the phrase “(renal cell)” that does not differentiate the enclosed subject matter as being required subject matter of the invention from being merely exemplary. It is unclear whether the limitation(s) within the parentheses are part of the claimed invention. See MPEP § 2173.05(d).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
7. Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
a) Claim 2 recites both kidney cancer and renal cell cancer. Kidney Cancer: Refers to a broader category of cancers that can originate in various parts of the kidney, including the renal pelvis and soft tissue. Renal Cell Carcinoma (RCC): A specific type of kidney cancer that develops in the lining of the renal tubules, accounting for about 85% of kidney cancer cases.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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
8. Claims 1-6 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim interpretation
The method invention is interpreted as being drawn to treating any cancer in a subject using glycan-engineered cancer-therapeutic antibody which is resistant to a genus of endoglycosidase S (endoS enzymes), and which endoS can be administered to the subject, in vivo, to effect a deglycosylation of endogenous serum antibodies, in order to mediate the cancer-therapeutic effect of the enzyme-resistant antibody in the subject.
treat/treatment: the specification does not teach or suggest prophylaxis or prevention as an outcome and/or overlapping with a therapeutic antibody. Accordingly, treatment is construed as therapeutic.
EndoS: the specification provides a detailed description of numerous examples of EndoS sequences and variants thereof starting at
[0096] EndoS is an endoglycosidase secreted by the human pathogen Streptococcus pyogenes. EndoS specifically hydrolyses the asparagine-linked glycan on IgG between the two core GlcNAc residues. The EndoS polypeptide is preferably S. pyogenes EndoS, or a variant or fragment of S. pyogenes EndoS which retains IgG endoglycosidase activity. The variant may be an EndoS polypeptide from another organism, such as another bacterium. The bacterium is preferably a Streptococcus, such as Streptococcus equi, Streptococcus zooepidemicus, or preferably, Streptococcus pyogenes. Alternatively, the variant may be from Cornyebacterium pseudotuberculosis, for example the CP40 protein; Enterococcus faecalis, for example the EndoE protein; or Elizabethkingia meningoseptica (formerly Flavobacterium meningosepticum), for example the EndoF.sub.2 from Elizabethkingia meningoseptic and CP40 from Corynebacterium pseudotuberculosis.
[0097] In one embodiment, the EndoS polypeptide may comprise:
[0098] (a) the amino acid sequence of SEQ ID NO: 1; [0099] (b) a variant thereof having at least 50% identity to the amino acid sequence of SEQ ID NO: 1 and having IgG endoglycosidase activity; or
[0100] (c) a fragment of either (a) or (b) having IgG endoglycosidase activity.
[0101] Preferably, the EndoS polypeptide comprises, or consists of, the sequence of SEQ ID NO: 1. SEQ ID NO: 1 is the sequence of the mature form of EndoS, without the signal sequence and corresponds to amino acids 37 to 995 of SEQ ID NO: 2.
[0102] The polypeptide may additionally include a signal sequence. Accordingly, the EndoS polypeptide may comprise:
[0103] (a) the amino acid sequence of SEQ ID NO: 2;
[0104] (b) a variant thereof having at least 50% identity to the amino acid sequence of SEQ ID NO: 2 and having IgG endoglycosidase activity; or
[0105] (c) a fragment of either (a) or (b) having IgG endoglycosidase activity.
The EndoS polypeptide may consist of the sequence shown in SEQ ID NO: 2.
[0106] Variant polypeptides are those for which the amino acid sequence varies from that in SEQ ID NO: 1 or SEQ ID NO: 2, but which retain the same essential character or basic functionality as EndoS. The variant polypeptides may therefore display IgG endoglycosidase activity. Typically, polypeptides with more than about 50%, 55%, 60% or 65% identity, preferably at least 70%, at least 75%, at least 80%, at least 85%, at least 90% and particularly preferably at least 95%, at least 97% or at least 99% identity, with the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2 are considered variants of the protein. Such variants may include allelic variants and the deletion, modification or addition of single amino acids or groups of amino acids within the protein sequence, as long as the peptide maintains the basic functionality of EndoS. The identity of variants of SEQ ID NO: 1 or SEQ ID NO: 2 may be measured over a region of at least 100, at least 250, at least 500, at least 750, at least 800, at least 850, at least 900, at least 950, at least 955 or more contiguous amino acids of the sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2, or more preferably over the full length of SEQ ID NO: 1 or SEQ ID NO: 2.
[0107] Variants of the amino acid sequence of SEQ ID NO: 1 preferably contain residues 191 to 199 of SEQ ID NO: 1, i.e., Leu-191, Asp-192, Gly-193, Leu-194, Asp-195, Val-196, Asp-107, Val-198, Glu-199, of SEQ ID NO:1 (which corresponds to residues 227 to 235 of SEQ ID NO:2, i.e. Leu-227, Asp-228, Gly-229, Leu-230, Asp-231, Val-232, Asp-233, Val-234 and Glu-235 of SEQ ID NO:2), These amino acids constitute a perfect chitinase family 18 active site, ending with glutamic acid. The glutamic acid in the active site of chitinases is essential for enzymatic activity. Most preferably, therefore, the variant of SEQ ID NO:1 contains Glu-199 of SEQ ID NO:1 and the variant of SEQ ID NO:2 contains Glu-235 of SEQ ID NO:2.
[0108] The fragment of the EndoS polypeptide used in the invention is typically at least 10, for example at least 20, 30, 40 or 50 more amino acids in length, up to 100, 200, 250, 300, 500, 750, 800, 850, 900, 950 or 955 amino acids on length, as long as it retains the IgG endoglycosidase activity of EndoS.
The specification does not support the myriad endoS enzymes having the full breadth of attributes required of the instant claimed method to place Applicants in full possession of the method invention. The interpretation encompasses a genus of EndoS structures beyond those taught in the specification. Because applicant seeks patent protection for all such endoS agents, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Disclosure in the Specification
The specification teaches using endoS from S. pyogenes of SEQ ID NO: 1 as follows on p. 38, lines 29-31:
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Figure 8 illustrates the principle behind the method invention as follows and on the specification at p. 39, lines 5-13:
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The specification demonstrates that oligomannose- engineered antibodies resist endoS enzymatic degradation, in vitro, on p. 41, line 9 to p. 41:
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The specification teaches hypothetical Examples 2-4 for the in vivo use of the endoS therapy in Examples 2-3, and extracorporeal use in Example 4 followed by a HER2-specific, glycol-engineered antibody.
The specification does not nearly test the genus of all possible endoS enzymes but only that of a protein enzyme for SEQ ID NO: 1 from S. pyogenes.
The specification does not nearly test the genus of all possible endoS variants or fragments much less that of any such sequence corresponding to SEQ ID NO:1 in any the in vitro bioassays for measuring reduced, non-specific serum Ig binding to FcR.
Applicants specification does not support the genus of endoS enzymes that can be used in vitro, in vivo, or extracorporeal that would deglycosylate any Ig in order to effectuate an anti-cancer therapeutic effect for any endo—resistant antibody, in vivo.
f) Predictability in the Art:
Applicants own specification discusses the caveats of enzyme-mediated approaches to reducing IgG binding to FcR at p. 4, lines 6-17:
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Applicants own specification teaches the importance and complexities of the kind of enzyme used, the resistance of the therapeutic antibody to that enzyme and the timing of the application of the enzyme on p. 4, lines 23-27:
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Applicants own specification narrows the success of the invention to endoS enzymes on p. 8, lines 16-20 and the working embodiments discussed above:
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Finally, and with respect to claims encompassing variants of any kind of enzyme much less that for the S. pyogenes enzyme of SEQ ID NO: 1, the decision from Novozymes is pertinent. In Novozymes A/S v. DuPont Nutrition Biosciences APS, Case No. 12-1433 (Fed. Cir., July 22, 2013) the Federal Circuit noted that the relevant question is not whether a person of ordinary skill in the art would have been enabled to identify specific variants within the scope of the claims, but instead, whether the specification actually discloses those variants to a person of skill in the art. To demonstrate actual possession of the claimed variants, "Novozymes [needed] to confirm its predictions by actually making and testing individual variants or at least identifying subclasses of variants that could be expected to possess the claimed properties."
Thus, based on the limited number of EndoS enzymes disclosed in the specification that have the attributes (structure/function correlation) for at least a reasonable scope of the claimed method invention, that being in vitro, and effecting non-specific, endogenous Igs from blocking or competing for binding with intended or desired antibody binding, the ordinary artisan would conclude that applicants were not in possession of the full scope of the invention at the time of filing.
Enablement
9. Claims 1-6 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 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.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability of the art, the breadth of the claims, the quantity of experimentation which would be required in order to practice the invention as claimed.
Interpretation of the Claims
The interpretation of the claims is discussed above. IN addition, the claims are drawn to the method requiring a treatment effect for any cancer using an anti-cancer therapeutic antibody, trastuzumab, endoS-resistant, glycol-engineered antibodies following in a time-sensitive manner, any endoS 1) pre-treatment step occurring, in vivo, or extra corporeal, to the administration of the antibody to mediate a therapeutic anti-cancer effect.
Disclosure in the Specification
As discussed above, the specification described the protocol for the method envisioned in Figure 8 and the hypothetical steps for implementing the method in Examples 2-4. There are no single working examples of in vivo administration for the genus of enzymes encompassed by the claims that would have the de-glycosylation-reducing effect on endogenous Igs, to the extent that Applicants have shown a preferred enzyme, the importance of its bioavailability, in vivo, and the outcome of achieving therapeutic effects for cancer-therapeutic antibody, trastuzumab, in vivo, following the, in vivo or extra corporeal, treatment of the subject.
IN addition, the NCBI® protein sequence database reveals 65 different endoS enzymes from various species, and for the ordinary artisan to have selected any endoS enzyme to consider in the first step of the invention, would require undue experimentation.
In addition, the implement the step of endoS treatment, either in vivo or extra corporeal, would have required that the ordinary artisan consider the importance of the timing between the endoS versus antibody administration, again adding to the amount of additional experimentation needed to evaluate the enablement of the instant claim scope.
Finally, the ordinary artisan would have had a choice of oligomannose-type modifications to make to the genus of therapeutic antibodies to generate one resistant to the genus of enzymes, and to test whether its general or specific therapy was effective in vivo in order to treat any cancer.
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19, 24 (CCPA 1970). "[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.'" Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993)).
Prior Art Status: Translation of Therapeutics from In vitro to In vivo is Unpredictable
The prediction of drug effects in an animal subject based solely on in vitro cell based assays as in the present case is not reliable and further evaluation in animal tumor systems is essential. The method is not a single step procedure but one calculated to generate a therapeutic antibody engineered to be resistant to a genus of endoS enzymes, in order that a pre-treatment of a cancer-effected patient with the genus of endoS, would results in therapeutic efficacy of that very antibody against a cancer after a calculated time period between endoS treatment and antibody administration. Thus, in general, immunotherapy is an unpredictable art field.
Further, inasmuch as in vivo animal drug testing may be a platform technology in a determination of enablement, the complexity and difficulty of drug delivery for cancer treatment is underscored by Voskoglou-Nomikos (Clin. Can. Res. 9:4227-4239 (2003)). Voskoglou-Nomikos conducted a study using the Medline and Cancerlit databases as source material in comparing the clinical predictive value of three pre-clinical laboratory cancer models: the in vitro human cell line (Figure 1); the mouse allograft model; and the human xenograft model (Figures 2 and 3). Significantly when each of the cancer models was analyzed against Phase II activity, there was a negative correlation for the in vitro human cell line models being predictive of good clinical value. No significant correlations between preclinical and clinical activity were observed for any of the relationships examined for the murine allograft model. And the human xenograft model showed good tumor-specific predictive value for NSCLC and ovarian cancers when panels of xenografts were used, but failed to predict clinical performance for breast and colon cancers. Voskoglou-Nomikos suggests that “the existing cancer models and parameters of activity in both the preclinical and clinical settings may have to be redesigned to fit the mode of action of novel cytostatic, antimetastatic, antiangiogenisis or immune-response modulating agents” and “New endpoints of preclinical activity are contemplated such as the demonstration that a new molecule truly hits the intended molecular target” (p.4237, Col. 1, ¶6).
Dennis (Nature 442:739-741 (2006)) also recognizes that human cancer xenograft mouse models for testing new drugs has been and will remain the industry standard or model of choice, but it is not without problems because “many more [drugs] that show positive results in mice have little or no effect in humans” (p. 740, Col. 1, ¶3). Dennis describes transgenic animal mouse models as an alternative to xenograft modeling and the general differences between mice and humans when it comes to tumor modeling: 1) cancers tend to form in different types of tissue, 2) tumors have fewer chromosomal abnormalities, 3) ends of chromosomes (telomeres) are longer, 4) telomere repairing enzyme active in cells, 5) short lifespan, 6) fewer cell divisions (1011) during life than humans (1016), 7) metabolic rate seven time higher than humans, and 8) lab mice are highly inbred and genetically similar.
Cespdes et al. (Clin. Transl. Oncol. 8(5):318-329 (2006)) review the some of the examples of art-recognized animal disease model correlates for the corresponding human disease in Tables 1-3. Cespedes emphasizes the challenges in using animal models as predictive correlates for human responsiveness to therapeutics and sets forth on pp. 318-319 a list of criteria that would represent the ideal in vivo model for studying cancer therapeutics. As regards the use of xenograft modeling, Cespedes teaches:
"One limitation of the xenograft models is precisely their use of an immunocompromised host, which eliminates the possibility of studying the role of the immune system in tumor progression. Some authors also think that cancer and host cells being from different species may limit the occurrence of critical tumor-stroma interactions, leading to an inefficient signaling. The organ of implantation could also become a limitation to the system. Thus, as it has already been described, subcutaneous xenografts infrequently metastasize and are unable to predict response to drugs” (p. 325, Col. 1, ¶2).
One skilled in the art would reasonably conclude that evidence obtained in any in vitro assay would not even necessarily correlate with results expected in any animal model. Thus to the extent the claims encompass an intended in vivo treatment effect of any subject, and the specification does not provide sufficient guidance using the genus of endoS enzyme in combination with the glycol-engineered, endoS-resistant trastuzumab antibody in a method in vivo to treat any cancer much less breast, the POSA could reasonably conclude that Applicants were not in possession of the full scope of the invention at the time of filing.
Therefore, due to the unpredictability of immunotherapeutics in general and in view of the insufficient guidance and/or working examples concerning the use the trastuzumab antibody as an immunotherapeutic agent in vivo in combination with the second agents, i.e., endoS enzymes, one skilled in the art would reasonably conclude that the broadly claimed invention was not fully supported in the specification, and thereby removing applicants from full possession of the invention.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained through the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
10. Claims 1-6 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Preither et al. (Molec. Immunol. 43(8):183-1193 (2006); IDS 8/21/2023) in view of Nandakumar et al. (TRENDS IN IMMUNOLOGY, ELSEVIER LTD. TRENDS JOURNALS, GB, vol. 29, no. 4, 6 March 2008 (2008-03-06), pages 173-178); IDS 8/21/2023) and Hodoniczky et al (Biotechnol. Prog. 2005,21, 1644−1652).
The claimed method for therapeutic efficacy of a therapeutic antibody, trastuzumab, administered to a subject following after some time interval, the administration of an EndoS agent that reduced FcR binding of endogenous serum antibodies was prima facie obvious at the time of the invention over the teachings of Preithner and Nandakumar.
AS regards claims 1 and 6, Preither teaches trastuzumab as a prototype in its analysis of the effect of competing endogenous antibodies on the therapeutic effect, thus directly providing a motivation to reduce endogenous antibody binding to FcR in order for trastuzumab to mediate an effect on a cancer relevant cell type such as breast cancer.
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and on p. 1184, Col. 2:
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Preither teaches trastuzumab as a prototype in its analysis of the effect of competing endogenous antibodies on the therapeutic effect, thus directly providing a motivation to reduce endogenous antibody binding to FcR in order for trastuzumab to mediate an effect on a cancer relevant cell type such as breast cancer.
As regards Claims 1 and 4-5(a), Hodoniczky teaches glycoengineering of Herceptin/trastuzumab by introduction of mannose and GlcNac residues in Figure 2 for glycoforms comprising mannose (3 residues) and GlcNac bisecting with mannose. Hodoniczky teaches a bisecting ‚1,4-linked GlcNAc to the core ‚-linked mannose of degalactosylated Mab Herceptin results control the therapeutic efficacy of Mabs in vivo and to offer a more “humanized” glycoform profile for recombinant Mab products such as increasing ADCC. The mannose/GlnAc glycoform profile for Herceptin/ trastuzumab would posses the inherent property of being resistant to the endoS thus providing the motivation to consider an enhanced ADCC effect via the blocking endogenous competitive Ig in view of Priether and Nandakumar.
AS regards claims 1-2, Nandakumar teaches that the endoglycosidase S can be used for an in-vivo treatment of auto- immune diseases mediated by pathogenic antibody-mediated inflammation; that endoS has been successfully used in an in-vivo arthritis model. Nandakumar suggests the use of bacterial enzymes removing the carbohydrate moieties of immunoglobulins as an antidote against severe side-effects observed with therapeutic antibodies including those in cancer therapies.
Nandakumar teaches on p. 177, Col. 1-2:
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As regards claim 3, Nandakumar teaches “transient” use of endoglycosidase. As explained above, the claimed method is not so limited as to the criticality of the “set time interval” with respect to increasing the potency of the therapeutic antibody. Even, assuming arguendo, that the time period is related to therapeutic antibody potency, then Under MPEP 2144.05, differences in ranges such as time, concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960) (MPEP 716.02(d)).
The ordinary artisan would have been motivated and assured of reasonable success in having produced the method for increasing potency of a glycol-engineered trastuzumab/Herceptin antibody administered to a subject following after some time interval, the administration of an endoS agent that reduced FcR binding of endogenous serum antibodies based on the combined teachings of Preithner, Nandakumar and Hodoniczky with outcomes recognized as enhanced ADCC in cancer therapy. Each of the references recognizes and appreciates the inherent disadvantages of endogenous serum antibodies under pathological conditions such as cancer or autoimmunity insofar as those antibodies being pathogenic themselves or in blocking/competing for critical essential Fc receptors to which intended therapeutic antibodies would bind.
This blocking or competition is taught to be disadvantageous by Preithner with respect to the amount of therapeutic antibody that must be used in order to effectively compete for FcR binding with endogenous antibodies. Preithner teaches the removal of endogenous antibodies can be achieved by chromatography using SpA protein, while Nandakumar goes beyond Preithner in its appreciation and teaching of the removal of competing or deleterious endogenous antibodies using the method of EndoS. Nandakumar teaches that EndoS can be administered in vivo to block endogenous antibody function and Fcr binding. Thus, to improve the potency of a therapeutic antibody vis-à-vis the treatment of serum in vitro or by administration of an agent in vivo that reduces endogenous antibody binding to FcR such as EndoS as taught by Nandakumar would have been sufficient motivation to have produced the instant claimed method.
The references provide the teachings for detailed methods and reagents that can be used to perform the method steps, that EndoS has been used in vivo to consider its effect on endogenous antibody binding to FcR, thus the ordinary artisan would have been reasonably assured of success in having produced the instant claimed method at the time of the invention.
Conclusion
11. No claims are allowed.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached on Mon-Fri 9 AM-5 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643