DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - Rejection under the Judicially Created Doctrine of Improper Markush Grouping
Claims 1, 2 and 9-21 are rejected under the judicially created doctrine of "improper Markush grouping". The Markush group of Formula (VIII) contains a plethora of nested variables. This is an improper grouping of alternatively useable species. MPEP 803.02 describes a Markush grouping as " ... "selected from the group consisting of A, Band C." The examiner respectfully directs the Applicant's attention to MPEP 803.02 shown below for convenience:
"A Markush-type claim recites alternatives in a format such as "selected from the group consisting of A, Band C." See Ex parte Markush, 1925 C.D. 126 (Comm'r Pat. 1925). The members of the Markush group (A, B, and C in the example above) ordinarily must belong to a recognized physical or chemical class or to an art-recognized class. However, when the Markush group occurs in a claim reciting a process or a combination (not a single compound), it is sufficient if the members of the group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of
them possess this property. Inventions in metallurgy, refractories, ceramics, pharmacy, pharmacology and biology are most frequently claimed under the Markush formula but purely mechanical features or process steps may also be claimed by using the Markush style of claiming. (See MPEP § 2173.05(h))."
Furthermore, the members of a proper Markush grouping " ... ordinarily must belong to a recognized physical or chemical class or to an art-recognized class." MPEP 803.02 also states that members of a Markush grouping are " ... sufficiently few in number or so closely related that a search and examination of the entire claim can be made without serious burden." This paragraph of the MPEP is shown below for convenience: "If the members of the Markush group are sufficiently few in number or so closely related that a search and examination of the entire claim can be made without serious burden, the examiner must examine all the members of the Markush group in the claim on the merits, even though they may be directed to independent and distinct inventions. In such a case, the examiner will not follow the procedure described below and will not require provisional election of a single species. (See MPEP § 808.02.)"
A Markush claim contains an "improper Markush grouping" if:
1. The species of the Markush group do not share a "single structural similarity,"
- Meaning they do not belong to the same recognized physical or chemical class
or same art-recognized class (see explanation supra), or
2. The species do not share a common use,
- Meaning they are not disclosed in the specification or known in the art to be
functionally equivalent.
If 1 or 2 above apply to a Markush grouping, a rejection under the judicially approved "improper Markush grouping" doctrine is proper.
The antibodies of the rejected claims do not share a "single structural similarity" since there is no common core due to the wide range of antibodies possible given variables:
“…an antigen binding portion having at least 80% sequence identity to SEQ ID NO:11, and wherein the antibody or antigen-binding portion thereof comprises one or more heavy chain CDRs, wherein (i) a heavy chain CDR1 has at least 70% sequence identity to SEQ ID NO: 1, (ii) a heavy chain CDR2 has at least 70% sequence identity to SEQ ID NO: 2, and (iii) a heavy chain CDR3 has at least 70% sequence identity to SEQ ID NO: 3.”
For a Markush grouping to be proper, the alternatives represented by the grouping must have a "significant structural element that is shared by all of the alternatives" or the species must all share a common use and recognized as "functionally equivalent". A significant structural element that is shared by all of the alternatives here refers to cases where the antibodies share a common structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity.
Here, each alternative does not have a common structure which occupies a large portion of the structure or have a structurally distinctive portion in view of the prior art which is essential to the claimed common activity/properties in view of the variability in the anti-PD-L1 binding region.
Additionally, as a result of the wide range of antibodies possible by the instant Markush formula, each antibody does not belong to the same recognized physical or chemical class or to the same art-recognized class and no credible evidence for a common use amongst all claimed antibodies exists in the specification. A person of ordinary skill in the art would understand that antibodies with such greatly varied structure cannot be expected to have predictable properties. This is a central concept to basic organic chemistry and common knowledge of those with ordinary skill in the art.. Therefore, in the absence of evidence to the contrary, all antibodies within the metes and bounds of the extraordinarily large Markush grouping of the instant claims cannot be individually envisioned and each expected to be functionally equivalent.
This rejection may be overcome by either amending the claims to include only the antibody embodiments that share a single structural similarity and a common use such as the anti-PD-L1 binding portions corresponding to the SEQ ID’s that are clearly supported and enabled by the instant specification, within the meaning of section 112(a).
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, 2, 9-21 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.
The rejected claims cover anti-PD-L1 antibodies comprising an antigen binding portion having at least 80% sequence identity to SEQ ID NO:11, and wherein the antibody or antigen-binding portion thereof comprises one or more heavy chain CDRs, wherein (i) a heavy chain CDR1 has at least 70% sequence identity to SEQ ID NO: 1, (ii) a heavy chain CDR2 has at least 70% sequence identity to SEQ ID NO: 2, and (iii) a heavy chain CDR3 has at least 70% sequence identity to SEQ ID NO: 3, see also dependent claims.
To satisfy the written-description requirement, the specification must describe every element of the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention”); In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989) (“the description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed”).
With regard to the recited genus of antibodies having the above sequence identity, the following applies:
Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed. Cir. 2010) states that “...a generic claim may define the boundaries of a vast genus of chemical compounds...the question may still remain whether the specification, including the original claim language, demonstrates that the applicant invented species sufficient to support a claim to a genus”. See page 1171.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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 claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
See also Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a “laundry list” disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species.
Amgen, Inc. v. Chugai Pharmaceutical Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) states that “it is well established in our law that conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it”.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or structural features common to the members of the genus, which features constitute a substantial portion of the genus, so that one of skill in the art can “visualize or recognize” the members of the genus (Emphasis added). Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)(“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(i), the court states, "An 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."
Courts have stated that “[i]n claims involving [non-genetic] chemical materials, generic formulae usually indicate with specificity what the generic claims encompass. One skilled in the art can distinguish such a formula from others and can identify many of the species that the claims encompass. Accordingly, such a formula is normally an adequate description of the claimed genus.” Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). (emphasis added).
However, there is no such specificity here, nor could one skilled in the art identify the anti-PD-L1 antibodies encompassed by the claims. Specifically, Applicant fails to disclose any other antibodies, besides those covered by the specific SEQ ID NO’s in the specification, and in relation to the above, these disclosed species or subgenre do not represent the substantial variety covered by the genus of antibodies comprising the breadth of antibody embodiments allowed by the instant sequence identities.
With regard to the functional definition of the anti-PD-L1 antibody, the specification does not clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed (see Vas-Cath at page 1116) because the specification contains almost no information by which a person of ordinary skill in the art would understand that the inventors possessed the all of the recited antibodies. At best, it simply indicates that one should test an inordinate number of antibodies covered by the claims to see if the antibodies can perform the required binding to PD-L1.
Moreover, how much homology is required to claim a variant of a known nucleic acid sequence when the function of the nucleic acid is recited in the claims was directly answered by Ex parte Livshits (Appeal 2013-001807; US Patent Application 11/106,455):
https://www.bradley.com/insights/publications/2016/02/how-much-homology-is-enough-under--112
The answer in this case was no. The PTAB agreed with the Examiner that a PHOSITA could envision sequences that met the percent identity requirement and hybridized under the recited conditions to SEQ ID NO:3.
Further, the Examiner admitted that by using conservative substitutions, a PHOSITA could likely envision a DNA sequence that encoded a polypeptide having the same tertiary structure as the polypeptide encoded by SEQ ID NO:3.
However, the PTAB found there was no teaching that the conservation of structure (whether in the DNA or encoded polypeptide) would be a surrogate for conservation of the function claimed (over-expression of L-amino acids in the culture medium).
In other words, PTAB wanted some teaching as to which of the 5 pent of residues of the in the recited single domain antibody could be altered while still conserving the function of the encoded polypeptide.
The specification demonstrated the recited function for the polypeptide encoded by SEQ ID NO:3, but offered no teaching as to what regions of the recited protein were critical for conservation of the recited function and which regions could be modified.
The PTAB stated that the specification “leaves it to others to discover the nature and scope of substitutions, deletions, and insertions that can be made to arrive at a 95% homology sequence that additionally allows for recited activity.”
The applicants attempted to use BLAST homology data to argue that a PHOSITA would be able to address the issue, but the evidence was accorded little weight and characterized as an “invitation to experiment” by the PTAB.
The PTAB also noted that even though the DNA/polypeptides that could be envisioned by the PHOSTIA could be easily tested as set forth in the specification for conservation of the recited function, this was not enough to describe the structure so that a PHOSITA could determine “beforehand whether or not a particular structure meets the functional requirements.” As such, the PTAB held that for a nucleic acid variant which is claimed by homology and function of the expressed protein, the PHOSITA must be able to determine if the nucleic acids claimed produce a protein that accomplished the recited function from the specification itself in order to meet the written description requirement.
Therefore, in the instant case, a PHOSITA must be able to determine which antibodies can accomplished the recited anti-PD-L1 function from the specification itself in order to meet the written description requirement.
However, the specification here leaves it to others to discover the nature and scope of substitutions, deletions, and insertions that can be made to arrive at the recited sequence identity that additionally allows for anti-PD-L1 activity since the specification offered no teaching as to what regions sequence positions were critical for conservation of the recited function and which regions could be modified, see In re ’318 Patent Infringement Litigation, 583 F.3d 1317, 1327 (Fed. Cir. 2009) (“[A]t the end of the day, the specification, even read in light of the knowledge of those skilled in the art, does no more than state a hypothesis and propose testing to determine the accuracy of that hypothesis. That is not sufficient.”).
Even though the DNA/polypeptides that could be envisioned by the PHOSTIA could be easily tested as set forth in the specification for conservation of the recited function, this is not enough to describe the structure so that a PHOSITA could determine beforehand whether or not a particular structure meets the anti-PD-L1 functional requirements.
The Examiner acknowledges that a working example or exemplified embodiment is not necessarily a requirement for description. However, where a generic claim term is present in a claim, as in the present application, and defined only by functional characteristics, the specification must convey enough information, e.g., via sufficient representative examples, to indicate invention of species sufficient to constitute the genus. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 967 2 (Fed. Cir. 2002). The written description requirement “requires a description of an invention, not an indication of a result that one might achieve if one made that invention.” Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997); see also Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1350 (Fed. Cir. 2013) (“A patent...‘is not a reward for the search, but compensation for its successful conclusion.’ ... For that reason, the written description requirement prohibits a patentee from ‘leaving it to the ... industry to complete an unfinished invention.’” (citations omitted)).
However, the specification here lacks adequate written description for the recited anti-PD-L1 antibodies comprising an antigen binding portion having at least 80% sequence identity to SEQ ID NO:11, and wherein the antibody or antigen-binding portion thereof comprises one or more heavy chain CDRs, wherein (i) a heavy chain CDR1 has at least 70% sequence identity to SEQ ID NO: 1, (ii) a heavy chain CDR2 has at least 70% sequence identity to SEQ ID NO: 2, and (iii) a heavy chain CDR3 has at least 70% sequence identity to SEQ ID NO: 3; or the sequence identities in the dependent claims (e.g., 18-21).
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 2 and 9-21 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.
Claim 1 recites that the antibody or antigen-binding portion thereof has at least 80 % sequence identity to SEQ ID NO: 7. It is unclear what portion (HC, LC) comprises the recited portion.
Claim 1 recites an antibody or antigen-binding portion thereof has at least 80 % sequence identity to SEQ ID NO: 7, and wherein the antibody or antigen-binding portion thereof can specifically bind a programmed death-ligand 1 (PD-L1) polypeptide, and wherein the antibody or antigen-binding portion thereof comprises one or more heavy chain CDRs, each with 70% sequence identity to the recited sequences. It is unclear what portions of the antibody Applicant intends to cover that still retains anti-PD-L1 activity.
The claims are replete with “preferably” language. It is unclear if Applicant intends to limit the claims to the preferred embodiments.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 2, 9-17 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Publication No. 20170088620A1 based on an application by Nioi et al., as evidenced by See attached GenCore version 6.5.2; Copyright (c) 1993 – 2025; Biocceleration Ltd.; US-15-279-162; 2016-09-28; ASGR INHIBITORS; SEQ ID NO: 30152 (Nioi).
Regarding the antibody claims, Nioi teaches the required following single chain HC of anti-ASGR antibodies, with the required sequence homologies, including CDR sequence homologies (e.g. HC CDR 2, indicated below):
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See attached GenCore version 6.5.2; Copyright (c) 1993 – 2025; Biocceleration Ltd.; US-15-279-162; 2016-09-28; ASGR INHIBITORS; SEQ ID NO: 30152.
Treatment of cardiovascular disease is taught, see Abstract.
Any binding characteristic (claim 9) is a necessary aspect of these antibodies, or fragments thereof, see MPEP 2112.01.
Different antibody embodiments such a single-chain antibodies, fusion, or bispecific antibodies are within the purview of those of ordinary skill in order to enhance the therapeutic value of the antibody. In this manner, the difference between Nioi and the claimed inventions is that Nioi may not teach the invention with particularity so as to amount to anticipation (See M.P.E.P. § 2131: "[t]he identical invention must be shown in as complete detail as is contained in the ... claim." Richardson v. Suzuki Motor Co., 868 F.2d 1226, 1236, 9 USPQ2d 1913, 1920 (Fed. Cir. 1989). The elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990).). However, based on the above, Nioi teaches the elements of the claimed invention with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill (the prior art reference teaches or suggests all the claim limitations with a reasonable expectation of success. See M.P.E.P. § 2143).
Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Publication No. 20170088620A1 based on an application by Nioi et al., as evidenced by See attached GenCore version 6.5.2; Copyright (c) 1993 – 2025; Biocceleration Ltd.; US-15-279-162; 2016-09-28; ASGR INHIBITORS; SEQ ID NO: 30152 (Nioi) in view of Ueno et al., Cancer Res (2011) 71 (20): 6419–6427 (Ueno).
Nioi may fail to teach treatment of cancer. However, Ueno teaches that ASGPR as a novel important factor that responds to endogenous lectins in the tumor microenvironment to promote cancer metastasis by activating the EGFR–ERK pathway through interactions with counter-receptors on cancer cells, see abstract. In this way, those of ordinary skill could have applied inhibitors of this receptor in the manner required and in a predictable fashion for the purposes of treating cancers such as those of the CNS. Specifically, Ueno teaches the particular known technique of targeting ASGPR for cancer treatment was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying inhibitors of this receptor, such as those antibodies taught by Nioi, would have yielded predictable results. Accordingly, using the anti-ASGPR antibodies for the purposes of treating cancers, such as CNS cancers, would have been prima facie obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's acting supervisor, Janet Epps-Smith, can be reached at telephone number (571)272-0757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646