Commissioner’s Decision #1398
Décision du Commissaire #1398
TOPIC: B22 (not supported by disclosure), C00 (adequacy or deficiency of description)
SUJET: B22 (portée excessive), C00 (caractère adéquat ou inadéquat de la description)
Application No.: 2,451,493
Demande n°.: 2,451,493
IN THE CANADIAN PATENT OFFICE
DECISION OF THE COMMISSIONER OF PATENTS
Patent application number 2,451,493 having been rejected under subsection 30(3) of the Patent Rules, has subsequently been reviewed in accordance with paragraph 30(6)(c) of the Patent Rules. The recommendation of the Board and the decision are as follows:
Agent for the Applicant:
SMART & BIGGAR
55 Metcalfe Street Suite 900
PO Box 2999 Station D
Ottawa, Ontario
K1P 5Y6
Introduction
[1] Patent application number 2,451,493, entitled “CELL GROWTH INHIBITORS CONTAINING ANTI-GLYPICAN 3 ANTIBODY”, is owned by Chugai Seiyaku and Kabushiki Kaisha and stands rejected after the Applicant’s response to a Final Action as the Applicant’s response did not overcome the rejection. A review of the rejected application has therefore been conducted by the Patent Appeal Board pursuant to paragraph 30(6)(c) of the Patent Rules. For the reasons set out below, our recommendation is that the rejection ought to be withdrawn.
Background
The application
[2] The specification describes the use of anti-glypican-3 antibodies for inhibiting proliferation of liver and lung cancer cells expressing glypican-3. According to the background section of the description, the glypican family of cell surface proteins are thought to function as receptors for certain growth factors such as epidermal growth factor. Glypican-3 is a known member of this family and a glypican-3 gene has been isolated from a human gastric cancer cell line.
[3] More specifically, the description discloses mouse monoclonal antibodies (mAbs) specific for human glypican-3 that were prepared by immunizing mice with a peptide consisting of the amino acid sequence RQYSAYYEDLFIDKK, an amino acid sequence found in the known human glypican-3 protein.
[4] Two of the produced mouse mAbs, designated K6511 and K6534, demonstrated high binding activity to glypican-3 and were therefore selected for further in vitro antibody-dependent cell-mediated cytotoxic (ADCC) and complement-dependent cytotoxic (CDC) activity testing. The results of these tests indicate that a mouse anti-glypican-3 mAb exerts in vitro ADCC and CDC activities on a human liver cancer cell line. Other experimental results show that lung cancer cell lines also express glypican-3 on their surface. These experimental results favorably support a therapeutic utility for anti-glypican-3 antibodies in liver and lung cancer treatment.
[5] The specification further teaches that anti-glypican-3 antibodies of different types (i.e., humanized antibodies, chimeric antibodies and human antibodies) could also be used for inhibiting abnormal proliferation of liver and lung cancer cells expressing glypican-3 (see pages 4, 8, 11 and 12 of the description). For ease of reference, these antibody types are shown in Figure 1 (obtained from Patel and Goldberg, Cetuximab-Associated Infusion Reactions: Pathology and Management, Oncology, 2006 Oct; 20(11):1373-82).
Figure 1: Depiction of four types of therapeutic monoclonal antibodies based on protein composition (red shows animal portions; blue shows human portions)
[6] The standard procedure of producing monoclonal antibodies yields mouse (or “murine”) antibodies. Although murine antibodies are very similar to human ones there are differences, and the human immune system recognizes mouse antibodies as foreign, rapidly removing them from circulation and causing systemic inflammatory effects.
[7] The chimeric, humanized and human antibodies are types of monoclonal antibodies that circumvent the clinical problem of immune response to foreign mouse antibodies by reducing the amount of murine sequence from 100% (mouse monoclonal antibody) to about 30% (chimeric antibody) or 3% (humanized antibody) or to zero (i.e., fully human antibody) (see Animal Biotechnology: Models in Discovery and Translation, Academic Press, 2013, page 483).
[8] The specification ends with 20 claims, claiming pharmaceutical preparations comprising an anti-glypican-3 antibody for inhibiting abnormal proliferation of liver and lung cancer cells expressing glypican-3 and the use of an anti-glypican-3 antibody for related purposes.
Prosecution history
[9] Patent application 2,451,493 was filed in Canada on June 21, 2002 and published on January 3, 2003. Examination culminated with the issuance of a Final Action (FA) on February 4, 2014. The FA states that dependent claims 5, 10, 15 and 20 do not comply with section 84 of the Patent Rules and that the specification, insofar as it relates to these claims, does not comply with subsection 27(3) of the Patent Act.
[10] According to the Final Action, these defects were identified because these claims recite the use of a “humanized antibody” and the description fails to exemplify the use of humanized antibodies and fails to disclose the sequence information of the binding regions of a monoclonal antibody (the variable regions, or complementarity determining regions (CDRs)). The Final Action considered the Commissioner’s Decision in Re Sloan-Kettering Institute for Cancer Research (C.D. 1296) to stand for the proposition that the amino acid sequence information of the binding regions is required to adequately support claims reciting a humanized version of an antibody in absence of evidence that the humanized antibody had been made.
[11] In a letter of response to the FA dated July 31, 2014, the Applicant argued that the claims and description on file comply with section 84 of the Patent Rules and subsection 27(3) of the Patent Act as the requirements for sufficiency of disclosure had been met with regard to the humanized anti-glypican-3 antibodies. More specifically, the Applicant began by noting that the antigen has been specifically identified as glypican-3 in the specification. The Applicant then submitted that the person of ordinary skill in the art (POSITA) would have been able to produce humanized anti-glypican-3 antibodies by following only the instructions disclosed in the specification. Finally, the Applicant emphasized that the reliance on C.D. 1296 was misplaced in the context of the instant application.
[12] Unconvinced that the Applicant’s arguments rendered the application allowable, the Examiner forwarded the file to the Patent Appeal Board (the Board). The file included a Summary of Reasons (SOR) for maintaining that the application did not comply with the Patent Act and Patent Rules. The SOR stated that the application stood rejected on the same grounds and reasons as stated in the FA.
[13] In a letter dated October 25, 2014 wherein the SOR was enclosed, the Board offered the Applicant an opportunity to make further written submissions and/or attend an oral hearing.
[14] In a letter dated January 20, 2015, the Applicant informed the Board of its wish to provide additional written submissions before the panel commenced its preliminary review of the rejected application.
[15] Additional written submissions were received on September 18, 2015, which included further arguments as to why it would have been routine at the filing date of the instant application for the skilled person to produce a humanized anti-glypican-3 antibody based on the specification, which defined antigen glypican-3, and that an explicit disclosure of the antibody sequence was not necessary. Copies of relevant references were also provided.
[16] Although our invitation to attend an oral hearing was accepted by the Applicant, we do not consider an oral hearing to be required, in light of our recommendation that the rejection be withdrawn.
Issues
[17] Based on our reading of the FA, the SOR and the Applicant’s responses to both, the main issues raised in the FA and SOR are whether the specification complies with paragraphs 27(3)(a) and 27(3)(b) of the Act. More precisely: Would the recited humanized antibodies be correctly and fully described; and would the specification enable the POSITA to practice the invention as claimed without displaying inventive ingenuity or undertaking undue experimentation in circumstances where there is no evidence that a humanized antibody had been made and sequence information regarding the variable regions of an anti-glypican-3 antibody is not disclosed?
Legislation and legal principles
Purposive construction
[18] In accordance with Free World Trust v Électro Santé Inc, 2000 SCC 66 [Free World Trust] essential elements are identified through a purposive construction of the claims done by considering the whole of the disclosure, including the specification and drawings (see also Whirlpool Corp v Camco Inc, 2000 SCC 67 at paras. 49(f) and (g) and 52). In accordance with the Manual of Patent Office Practice §13.05 [revised June 2015; MOPOP], the first step of purposive claim construction is to identify the person skilled in the art and their relevant common general knowledge (“CGK”). The next step is to identify the problem addressed by the inventors and the solution disclosed in the application. Essential elements can then be identified as those elements of the claims that are required to achieve the disclosed solution.
Sufficiency of disclosure and enablement
[19] As noted above, the issue in the present case is whether the specification satisfies the requirements for sufficiency of disclosure under paragraphs 27(3)(a) and (b) of the Act, which read:
The specification of an invention must:
(a) correctly and fully describe the invention and its operation or use as contemplated by the inventor;
(b) set out clearly the various steps in a process, or the method of constructing, making, compounding or using a machine, manufacture or composition of matter, in such full, clear, concise and exact terms as to enable any person skilled in the art or science to which it pertains, or with which it is most closely connected, to make, construct, compound or use it;
[20] In regards to whether a specification complies with paragraphs 27(3)(a) and 27(3(b) of the Act, the courts have identified three relevant questions that must be answered by a reading of the specification: What is the invention? How does it work? Having only the specification, can the POSITA produce the invention using only the instructions contained in the disclosure? (Teva Canada Ltd. v. Novartis AG, 2013 FC 141 citing Teva Canada Ltd. v. Pfizer Canada Inc., 2012 SCC 60 and Consolboard v. MacMillam Bloedel, [1981] 1 S.C.R. 504 at 526, 56 C.P.R. (2d) 145). The first question is relevant to determining the nature of the invention and whether the specification “correctly and fully describe[s] the invention” as per paragraph 27(3)(a) of the Act. The other two questions are relevant to the enablement requirement under paragraph 27(3)(b) of the Act. These inquiries require fact-specific determinations.
[21] With regard to the third question, the POSITA must not be called upon to display inventive ingenuity or undertake undue, as opposed to routine, experimentation (Aventis Pharma Inc. v. Apotex Inc. 2005 FC 1283, Mobil Oil Corp. v. Hercules Canada Inc. [1995] F.C.J. No. 1243 and Merck & Co. v. Apotex Inc. [1995] 2 F.C. 723).
[22] According to Novartis Pharmaceuticals Canada Inc. v. Teva Canada Limited, 2013 FC 283, the relevant date for determining sufficiency of disclosure is the publication date of the application.
Humanized antibodies
[23] We are not aware of any specific guidance about humanized antibodies in the Canadian jurisprudence. As mentioned above, humanized antibodies were discussed in C.D. 1296. There is also a subsequent Commissioner’s Decision that we consider informative and helpful to the analysis of the instant case. In Re Immunex Corporation (C.D. 1302; see paras 67-68) the generic monoclonal antibodies that were the subject of the application were adequately described by the disclosure of a fully characterized antigen to which the antibody specifically binds:
However, there is specific and meaningful functional identity (specific immunoreactivity) between the two [antibody and antigen]– a fact that is exploited during the apparent routineness of the preparation of monoclonal antibodies.
…
Thus, the skilled person would appreciate that monoclonal antibodies can be adequately described based on a combination of a structural description of the antigen, functional identity between the antibody and antigen, and knowledge of predictable production methods.
…
[I]n cases where the antigen is a novel polypeptide and has been fully characterized, for example by complete amino acid sequence, a pioneering applicant can then claim monoclonal antibodies that are immunoreactive with the polypeptide without the applicant actually having made or deposited a specific embodiment. Such a claim would embrace, as subgenus of sorts, antibodies implicitly (or explicitly in the case of claim 58 for example) defined in relation to well-known monoclonal antibody production methods, which methods are understood to yield numerous species of monoclonal antibodies. Such a claim would not necessarily need to be restricted to any one species of monoclonal antibody since the skilled person would appreciate that there is neither commonality amongst the particular structures of the monoclonal antibodies’ binding regions (CDRs) nor a predictable structural relationship between such binding regions and their target epitopes.
As explained in more detail below, a similar rationale can be applied to the description of the humanized antibodies of the instant case.
Analysis
Purposive construction of the claims
The POSITA and the relevant common general knowledge (CGK) of this person
[24] In our view, the POSITA is a person practising in the fields of immunology and cancer therapy.
[25] For the present purpose and with respect to the CGK possessed by the POSITA, it is sufficient to say that the POSITA has CGK and technical experience for the production of therapeutic monoclonal antibodies of different types, including chimeric, humanized and human antibodies.
Terminology
[26] The following terms found in the claims or the description appear to have their ordinary customary meaning, as would be understood by the POSITA at the relevant date (see Maynard and Georgiou, Antibody Engineering, Annu. Rev. Biomed. Eng., 2000, 02:339-76).
Antibody: A large, Y-shaped protein that targets a specific antigen and that typically comprises two heavy chains and two light chains connected by disulfide bonds. The antigen binding region is found in the Fab portion of the antibody and the Fc portion plays a role in activation of complement and immune effectors cells. The term antibody encompasses all types of antibodies, including monoclonal, chimeric, humanized and human antibodies (all defined below).
Monoclonal antibody: A single antibody directed to a specific target epitope, typically produced by immunizing an animal with an antigen, recovering and fusing the spleen cells with immortalized cell lines to form individual hybridomas, each expressing a single antibody.
Chimeric antibody: An engineered antibody that is prepared by replacing the constant region of a foreign monoclonal antibody with a human constant region (see Figure 1).
Humanized antibody: An engineered antibody that is prepared by transplanting the CDRs of a monoclonal antibody developed in another species into a human acceptor monoclonal antibody (see Figure 1). The CDRs are short and variable stretches of amino acid residues that collectively interact with the target antigen. There are three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively, in the amino acid sequence of the variable domain of the heavy and light chains for a total of six CDRs per binding site. They are crucial to the specificity and the affinity of the antibody.
Human antibody: A fully human antibody that does not contain foreign parts (see Figure 1).
The problem to be solved and the proposed solution
[27] Having reviewed the application as a whole, it appears that the problem to be solved is a need for a new treatment for liver and lung cancers. The proposed solution is, broadly stated, the use of an anti-glypican-3 antibody to treat these conditions.
The essential elements of the claims that solve the identified problem
[28] Independent claims 1, 6, 11, and 16 read as follows:
1. A pharmaceutical preparation for inhibiting abnormal proliferation of hepatic cancer cells expressing glypican 3, which comprises: an anti-glypican 3 antibody, and at least one pharmaceutically acceptable carrier or additive.
6. A use of an anti-glypican 3 antibody for treating hepatic cancer.
11. A pharmaceutical preparation for inhibiting abnormal proliferation of lung cancer cells expressing glypican 3, which comprises: an anti-glypican 3 antibody, and at least one pharmaceutically acceptable carrier or additive.
16. A use of an anti-glypican 3 antibody for treating lung cancer.
[29] In light of the proposed solution, the POSITA would consider an anti-glypican-3 antibody to be an essential element that is common to the independent claims. The dependent claims 2-5, 7-10, 12-15 and 17-20 further specify the inherent cytotoxic activity of said essential anti-glypican-3 antibody or further define the antibody type.
[30] Rejected dependent claims 5, 10, 15 and 20 read as follows:
5. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the antibody is a humanized antibody or a chimeric antibody.
10. The use according to any one of claims 6 to 9, wherein the antibody is a humanized antibody or a chimeric antibody.
15. The pharmaceutical preparation according to any one of claims 11 to 13 wherein the antibody is a humanized antibody or a chimeric antibody.
20. The use according to any one of claims 16 to 18, wherein the antibody is a humanized antibody or a chimeric antibody.
[31] When the invention is practised in humans, it is clear from the specification and would be apparent to the POSITA that the use of mouse antibodies in such instances poses a secondary problem due to the human body’s immune reaction to foreign antibodies. The reduced immunogenicity of chimeric and humanized antibodies is thus advantageous for a continued therapeutic treatment of a human subject in order to minimize such an immune response. Accordingly, whether the humanized and chimeric antibodies recited in claims 5, 10, 15 and 20 are considered elements essential to solving the problem, or whether they are considered preferred embodiments, it remains that the central question in this case is whether humanized antibodies are correctly and fully described, and enabled.
[32] We also note that claims 5, 10, 15 and 20 encompass the use of a genus of humanized antibodies. In view of the solution provided, it is apparent that humanized antibodies need not be limited to one in particular or to those humanized antibodies having a special property other than the expected property of reduced immunogenicity in humans. In our view, the POSITA would understand from the description on page 6 that antibodies binding any glypican-3 epitope would be suitable to perform the claimed invention.
[33] The main issues are whether the specification complies with paragraphs 27(3)(a) and 27(3)(b) of the Act. More precisely: Would the recited humanized antibodies be correctly and fully described; and would the specification enable the POSITA to practice the invention as claimed without displaying inventive ingenuity or undertaking undue experimentation in circumstances where there is no evidence that a humanized antibody had been made and sequence information regarding the variable regions of an anti-glypican-3 antibody is not disclosed?
Commissioner’s Decision in Re Sloan-Kettering Institute for Cancer Research (C.D. 1296)
[34] The reasoning expressed in the FA indicates that the rejection is largely based on the findings and the conclusions reached in C.D. 1296. According to the FA, C.D. 1296 concluded that, based on the absence of CDR sequence information and a number of other factual considerations, the specification in that case neither adequately described nor enabled the POSITA to make a humanized version of the particular antibody there in issue. However, we consider that C.D. 1296 is of limited general applicability for at least the following reasons.
[35] The enablement requirement of paragraph 27(3)(b) of the Patent Act entails fact-specific determinations that take into account the CGK and the ordinary skills possessed by the POSITA at the publication date of the patent application. With this in mind, we note that C.D. 1296 dealt with a patent application that was filed on December 14, 1990, almost 12 years prior to the instant application and at that time, the humanization of murine monoclonal antibodies was not something routinely done. We note that there has been a significant evolution of the CGK between 1990 (the relevant date of C.D. 1296) and 2003 (the relevant date of the present case).
[36] The evolution of CGK is an important factor for assessing whether the disclosure in this case is sufficient to enable a person skilled in the art to practice the invention as claimed without displaying inventive ingenuity or undertaking undue experimentation as of the relevant date. In Whirlpool at para. 74, the Court said that the POSITA is thought to be reasonably diligent in keeping up with advances in the field to which the patent relates. The “common knowledge” of skilled workers undergoes continuous evolution and growth.
[37] With respect to whether the specification “correctly and fully” describes a humanized antibody as required by paragraph 27(3)(a) of the Act, C.D. 1296 leaves open the possibility that a humanized antibody can be described in ways other than by providing the amino acid sequences of the CDRs (see para. 62 of C.D. 1296). In line with the law and practices of other leading jurisdictions, Canadian examination practice with respect to antibodies has also evolved since C.D. 1296. For example, a previous decision of the Commissioner held that a mouse monoclonal antibody can be adequately described through reference to the antigen to which it specifically binds, provided the antigen has been fully characterized (e.g., through the provision of an amino acid sequence, see C.D. 1302 at para 68). We are of the view that the same principle may apply, by extension, to humanized antibodies.
[38] In our opinion, C.D. 1296 cannot impose a rigid rule that sequence information of the variable regions of a number of humanized antibodies must be provided in order to adequately describe and enable claims more generally reciting humanized versions of various murine antibodies that may bind to various epitopes of the same antigen.
[39] Beyond an evolution in the CGK, additional factual differences exist between C.D. 1296 and the present case. In particular, we observe that C.D. 1296 dealt with the humanization of a singular murine monoclonal antibody with unique binding properties that made it attractive as the basis for a therapeutic agent in comparison to other murine antibodies to the same target antigen. It is also relevant that the contemplated humanized antibody bound to a particular epitope found on an ill-characterized antigen. In that case, the antigen was not as well characterized as in the present case.
[40] In contrast, the claims at issue relate to humanized antibodies specific to a fully characterized antigen as alternatives to other types of antibodies, which were considered in the Final Action to be adequately described (through reference to the fully characterized antigen). As a result, to perform the claimed invention, it is apparent to the skilled person that the humanized antibodies need not be limited to one in particular or to those humanized antibodies having a special property other than the expected property of reduced immunogenicity in humans.
Enablement requirement under paragraph 27(3)(b) of the Act
[41] With regard to whether there is an enabling specification for the production of an antibody specific to the fully characterized and known human glypican-3, pages 5-12 of the instant description provide a detailed description of commonly known steps that can be used to produce a mouse monoclonal anti-glypican-3 antibody, a chimeric monoclonal anti-glypican-3 antibody and a humanized anti-glypican-3 antibody. The description also discloses the production of two mouse monoclonal antibodies designated K6511 and K6534 that display in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activity.
[42] The Applicant further submitted in its written submissions that, by at least 2002, the techniques for producing humanized antibodies were well established such that the production of humanized antibodies was considered “routine” by the POSITA. In this regard, the Applicant relied on several reference documents (e.g., various patents and sections of textbooks) to establish the state of the art with respect to humanization of antibodies as of the filing date of the instant patent application.
[43] Based on the instant description and Applicant’s submissions, we are satisfied that the state of the art for humanizing antibodies evolved since the early reports of successful production of humanized antibodies, but the broad steps for their production remain essentially the same:
i) Produce and isolate a hybridoma cell that can secrete a monoclonal antibody specific for the target antigen.
ii) Clone the variable regions of the monoclonal antibody produced by the hybridoma and obtain the sequence information to identify the CDRs.
iii) Graft the CDRs into appropriate expression vectors in combination with human antibody scaffolds to produce the humanized antibody.
[44] What significantly changed between the publication date of the application at issue in C.D. 1296 and the publication date of the present case is how routine the production of humanized monoclonal antibodies became. We are satisfied that, as of the publication date of the present application in 2003, a POSITA having only the specification and beginning with the fully characterized antigen would not have to undertake undue experimentation or display inventive ingenuity to produce a humanized antibody specific for glypican-3. This is supported by the understanding that many antibodies had been successfully humanized before 2002 (see O’Brien and Jones, Humanising Antibodies by CDR Grafting, Antibody Engineering, 2001; pages 567-590, particularly page 568).
Correct and full description under paragraph 27(3)(a) of the Act
[45] With regard to the requirement to correctly and fully describe the invention under paragraph 27(3)(a) of the Patent Act, we consider that the specification does not need to disclose the CDRs if the humanized antibodies recited in the claims are adequately described in other terms.
[46] As discussed above, in C.D. 1302, the Commissioner considered that a mouse monoclonal antibody was correctly and fully described through reference to the antigen to which it specifically binds, because the antigen had been fully characterized (even though the specification did not provide evidence that the monoclonal antibody had been made).
[47] It is our understanding that the outcome in C.D. 1302 was at least based on a recognition of a direct structural relationship and a specific and meaningful functional identity between the antigen and the corresponding antibody. Such structural relationship is unique to an antibody and its specific antigen as it is exploited during the preparation of monoclonal antibodies.
[48] The key difference between monoclonal antibodies and their humanized versions is in their method of production; they do not differ in their respective critical binding regions because the humanization process preserves the structural relationship with the target antigen. If the making of humanized antibodies from a fully characterized antigen had become routine by the relevant date, then it is our view that the same rationale that permits monoclonal antibodies to be adequately described through reference to the fully characterized antigen to which they specifically bind ought to logically also apply to satisfy the requirement to correctly and fully describe generic humanized antibodies.
[49] In the instant case, the scope of the claims in respect of the target polypeptide is limited to the known and fully characterized antigen glypican-3 and we consider that this provides a correct and full description of the corresponding monoclonal antibodies and by extension the humanized derivatives.
[50] In view of the above, we find that the specification is compliant with the requirements of paragraphs 27(3)(a) and 27(3)(b) of the Patent Act. The specification correctly and fully describes the invention encompassed by rejected claims 5, 10, 15 and 20 and enables the POSITA to make the recited humanized antibodies in order to practice the invention as claimed without inventive ingenuity or undue experimentation. It follows from these findings that we are also satisfied that claims 5, 10, 15 and 20 are fully supported by the description and comply with section 84 of the Patent Rules.
Conclusion
[51] Based on our review of the facts of this case, we have reasonable grounds to believe that the application complies with the Patent Act and Patent Rules.
Recommendation
[52] For the reasons set out above, we are of the view that the rejection is not justified on the basis of the defects indicated in the Final Action notice and have reasonable grounds to believe that the application complies with the Patent Act and the Patent Rules. We recommend that you notify the applicant in accordance with subsection 30(6.2) of the Patent Rules.
Marcel Brisebois Ed MacLaurin T. Nessim Abu-Zahra
Member Member Member
Decision
[53] I concur with the findings and the recommendation of the Board. In accordance with subsection 30(6.2) of the Patent Rules, I hereby notify the Applicant that the rejection of the application is withdrawn, the application has been found allowable and I will direct my officials to issue a Notice of Allowance in due course.
Johanne Bélisle
Commissioner of Patents
Dated at Gatineau, Quebec,
this 10th day of May, 2016