Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claims 6 and 7 are objected to because of the following informalities: Each of the antibody embodiments recited therein omits a conjunction between the VH and VL chains (claim 6) or the heavy and light chain regions (claim 7), which For clarity and readability, Applicant is requested to insert “and” between the VH and VL chains in each listed embodiment of claim 6 as well as between the HC and LC chains in each listed embodiment of claim 7. Appropriate correction is required.
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.
Written Description
Claims 9 and 26 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.
Claim 9 (which depends on claim 5) encompasses human LIFR antigen binding proteins that are, in some embodiments, heavy chain antibodies, single domain antibodies, and/or polyclonal antibodies. However, the human LIFR antigen binding proteins of the claimed invention are conventional monoclonal antibodies having at least six CDRs required for antigen binding. Thus, the heavy chain only/single domain antibodies having less than six CDRs required for antigen binding are not expected to bind to human LIFR commensurate in scope of the claims. Further, the recitation or disclosure of the claimed monoclonal antibodies does not provide written description support for polyclonal antibodies, which are structurally and functionally distinct.
Claim 26 recites a method of treating an LIFR-positive related disease comprising administering the human LIFR antigen binding protein of claim 5; however, the specification fails to identify LIFR-positive diseases beyond cancer that can be effectively treated with the claimed antibodies.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus (MPEP 2163).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description 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.” Id. at 1566, 43 USPQ2d at 1404 (quoting at 1171, 25
USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
Claim 9 is drawn to a human LIFR antigen binding protein comprising a heavy chain antibody, a single domain antibody, and/or a polyclonal antibody.
It is well-known in the art that, in order to bind antigen, a conventional antibody or antigen- binding fragment must have six complementarity defining regions (CDRs) (Janeway, see selection, in particular section 3-6). Because CDRs from both VH and VL domains contribute to the antigen- binding site, it is the combination of both the heavy and the light chain, and not either alone, that determines the final antigen specificity. The claimed human LIFR antigen binding proteins are conventional antibodies that require six CDRs as stipulated in the independent claim; yet, the antigen-binding proteins can be either a single domain antibody (VH or VL) or heavy-chain only antibody having at most only three CDRs per claim 9 (see Bates et al, Section 2.3.2). However, artisans would not reasonably expect the structure of only a single domain of the claimed human LIFR antibodies to have the functional property of binding to the target antigen.
Further, the anti-LIFR antibodies recited in claim 5 were generated using H2L2 humanized transgenic mice (Harbour BioMed), followed by single-B-cell sequencing and are thus monoclonal antibodies which target a single epitope of an antigen (Examples 1-3 of Specification). As such, the anti-LIFR antibodies cannot be polyclonal as recited in claim 9; and the recitation or disclosure of monoclonal antibodies does not provide written description support for polyclonal antibodies, which are structurally and functionally distinct since they bind to multiple epitopes on an antigen.
Claim 26 is broadly drawn to a method for treating an LIFR-positive related disease comprising administering an effective amount of the human LIFR antigen binding proteins recited in claim 5 to a subject in need thereof.
While the specification teaches that leukemia inhibitor factor (LIF) signaling is involved in cancer and provides examples of treating certain tumor types in vivo using the claimed anti-LIFR antibodies, particularly clones PR300516 or PR301168 (Example 7), the specification does not identify any non-cancer LIFR-positive diseases in which LIF/LIFR signaling plays a pathogenic role and thus would receive therapeutic benefit from the claimed methods. For example, LIFR expression is elevated on immune cells of patients with Multiple Sclerosis (MS) (Janssens et al, see Abstract and Introduction), yet LIF/LIFR signaling in the CNS is generally considered anti-inflammatory and neuroprotective (see, e.g. Davis et al, in particular, Abstract and Introduction; Janssens et al, in particular, Introduction). Consistent with this, preclinical studies in EAE models of MS show that CNS-targeted delivery of LIF reduces disease severity and promotes remyelination (Janssens et al, see Abstract and Introduction). Thus, although MS may be considered an LIFR-positive disease, inhibition of LIF/LIFR signaling with the claimed antibodies would likely not be effective for treating MS. Without further guidance provided by the specification, the full scope of LIF-positive diseases/disorders that can be effectively treated by the claimed methods remains unclear. As such, artisans would have to engage in additional, unpredictable basic science research identify LIFR-positive diseases wherein LIFR expression is not merely correlative but causative of disease pathology and thus would receive therapeutic benefit from the claimed methods.
Therefore, one of ordinary skill in the art would reasonably conclude that the Applicant was not in possession of the full breadth of 1) antigen binding proteins that are heavy-chain antibodies, single domain antibodies, or polyclonal antibodies that bind to human LIFR commensurate in scope of the claims or 2) LIFR-positive disease that can be treated by the claimed methods.
Examiner suggestion: Applicant may overcome rejection by removing reference to heavy chain, single domain, and polyclonal antibodies in claim 9 and amending claim 26 to recite ‘wherein the LIFR-positive disease is a tumor’.
Enablement
Claims 9, 26, 27, and 32 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.
Claim 9 is drawn to a human LIFR antigen binding protein comprising a heavy chain antibody and/or a single domain antibody.
As stated earlier, in order to bind antigen, a conventional antibody or antigen- binding fragment must have six complementarity defining regions (CDRs) (Janeway, see selection, in particular section 3-6). The claimed human LIFR antigen binding proteins are conventional antibodies that require six CDRs as stipulated in the independent claim; yet, the antigen-binding proteins can be either a single domain antibody (VH or VL) or heavy-chain only antibody having at most only three CDRs per claim 9 (see Bates et al, Section 2.3.2) (Bates, Adam, and Christine A. Power. "David vs. Goliath: the structure, function, and clinical prospects of antibody fragments." Antibodies 8.2 (2019): 28.). However, artisans would not reasonably expect only a single domain of the claimed human LIFR antibodies to have the functional property of binding to the target antigen absent of evidence provided in the specification.
Further, the anti-LIFR antibodies recited in claim 5 were generated using H2L2 humanized transgenic mice (Harbour BioMed), followed by single-B-cell sequencing and are thus monoclonal antibodies which target a single epitope of an antigen (Examples 1-3 of Specification). As such, the anti-LIFR antibodies cannot be polyclonal as recited in claim 9.
Claim 26 is broadly drawn to a method for treating an LIFR-positive related disease comprising administering an effective amount of the human LIFR antigen binding proteins recited in claim 5 to a subject in need thereof.
First, there is no evidence that each of the claimed human LIFR antigen binding proteins recited in claim 5 –particularly clone PR301127 --can treat an LIFR-positive related disease such as a tumor. The specification teaches that the claimed anti-human LIFR antibody clones—PR300516 (VH/VL chain of SEQ ID NOs: 46 and 40); PR301127 (VH/VL chain of SEQ ID NOs: 58 and 66 ); PR301152 (VH/VL chain of SEQ ID NOs: 50 and 63); PR301211 (VH/VL of SEQ ID NOs: 55 and 67); and PR301168 (SEQ ID NOs: 48 and 62) (Table 1)— were assessed for their ability to block the interaction between LIF and LIFR/gp130 (Example 4.4, pages 45-46). Of these clones, PR301127 did not significantly blocked LIF binding to LIFR/gp130 (see Figure 3 and Table 5). Moreover, clone PR301127 did not appear to inhibit LIF-induced phosphorylation of STAT3 compared to the positive control MSC-1 (anti-LIF Ab) in several tumor types, including Capan-2 pancreatic cancer cells, MDA-MB-231 breast cancer cells, as well as A549 and NCI-H292 non-small cell lung cancer cells (Example 5, see Figure 4. Note: densitometric or other quantitative analyses of the western blot data is not provided. However, it is readily apparent from qualitative assessment that clone PR301127 does not inhibit LIF-induced STAT3 phosphorylation in the selected tumor cells). Coupled with its inability to block the interaction between LIF and LIFR/gp130, there is insufficient evidence to support the therapeutic potential of clone PR301127 for the treatment of any LIF-positive disease, particularly LIF-positive tumors. Without further evidence, artisans would not reasonably expect all of the human LIFR antigen binding proteins encompassed by claim 5—specifically clone PR301127— to be able to effectively treat LIFR-positive diseases, including tumors. Claims 27 and 32 (which depend directly or indirectly on claim 26) also encompass the use of clone PR301127 in the treatment of LIFR-positive diseases and thus are further rejected.
Second, while the specification teaches that the LIF signaling pathway is involved in cancer and provides examples of treating LIFR-positive tumors in vivo using the anti-LIFR clones PR300516 or PR301168 (Example 7), there is no evidence demonstrating that the claimed human LIFR antigen binding proteins can effectively treat “LIFR-positive diseases” beyond cancer. LIFR expression alone is insufficient to establish that inhibition LIF/LIFR signaling with the claimed antibodies would be therapeutically beneficial across all “LIFR-positive” diseases. For example, LIFR expression is elevated on immune cells of patients with Multiple Sclerosis (MS) (Janssens et al, see Abstract and Introduction), yet LIF/LIFR signaling in the CNS is generally considered anti-inflammatory and neuroprotective (see, e.g. Davis et al, in particular, Abstract and Introduction; Janssens et al, in particular, Introduction). Consistent with this, preclinical studies in EAE models of MS show that CNS-targeted delivery of LIF reduces disease severity and promotes remyelination (Janssens et al, see Abstract and Introduction). In light of the above, although MS may be considered an LIFR-positive disease, a skilled artisans would not reasonably expect the inhibition of LIF/LIFR signaling with the claimed antibodies to be effective for treating MS. Thus, without further guidance provided in the specification, artisans would have to engage in additional unpredictable basic science research and experimentation to identify which LIFR-positive diseases – beyond cancer – can be effectively treated by the claimed antibodies.
Therefore, the specification is not enabling over the full scope of the claims.
Examiner suggestion: Applicant may overcome rejection by removing reference to heavy chain, single domain, and polyclonal antibodies in claim 9 and amending claim 26 to recite ‘wherein the LIFR-positive disease is a tumor’. Additionally, claim 26 can be further limited to human LIFR antigen binding proteins for which there is sufficient evidence demonstrating therapeutic potential against LIFR-positive tumors.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6 and 7 are 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 6 and 7 recite the broad recitation of a VH, VL, HC, or LC domain each having at least 70% identity to the recited sequences, and the claim also recites higher percent identity ranges (e.g. “at least 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity”), which are narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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.
Claim 9 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. Claim 9, which depends on claim 5, recites that the human LIFR antigen-binding protein can, in some embodiments, be a heavy chain antibody, a single domain antibody, or a polyclonal antibody. However, the human LIFR antigen binding proteins recited in claim 5 are conventional antibodies or antigen-binding fragments having six non-degenerate CDRs required for antigen binding (see, also, Examples 1-3 of Specification). These antibodies were generated using H2L2 humanized transgenic mice (Harbour BioMed), followed by single-B-cell sequencing and are thus monoclonal antibodies which target a single epitope of an antigen (Examples 1-3 of Specification). As such, human LIFR antigen binding proteins that are a) heavy chain only/single domain antibodies having at most three CDRs or b) polyclonal antibodies capable of recognizing multiple epitopes of an antigen do not incorporate all of the limitations of the independent claim. 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.
Conclusion
Claims 5, 8, 10-19,25 and 33 are allowable. Claims 6, 7, 9, 26, 27, and 32 are not allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641