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 .
THIS IS A SECOND NONFINAL OFFICE ACTION.
Election/Restrictions and Claim Status
Applicant’s election without traverse of Group I, claims 1-18, in the reply filed on 12/2/24 is acknowledged.
Claims 21-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/2/24.
Following the 5/5/25 Notice that the 12/2/24 reply was not fully responsive, see also 5/5/25 Interview Summary, applicant on 5/8/25 further elected the following single species:
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Applicant’s election of the above single species in the reply filed on 5/8/25 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 8, 9, 11 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made per above without traverse in the reply filed on 5/8/25.
Please note that claim 9 is withdrawn because this claim requires a combination of amino acid sequences of SEQ ID NO:4 and SEQ ID NO:9, which was elected, only SEQ ID NO:9 amino acid sequence was elected as the artificial Proline-Rich peptide.
CLAIMS STATUS in view of the above: Claims 1-7, 10, and 13-18 are under instant examination, whereas claims 8, 9, 11, 12 and 21-26 are withdrawn on bases as set forth above.
Priority
The instant application, filed 09/24/2021 is a National Stage entry of PCT/EP2020/057281 , International Filing Date: 03/17/2020
claims foreign priority to 19165892.1, filed 03/28/2019.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 8/28/25 Information Disclosure Statement, and provides a signed and dated copy of such herewith.
Claim Objections
Response to Arguments
Applicant’s arguments, see page 6, filed 8/28/25, and claim amendments with respect to the objections to claims 1, 2, 4 and 16 have been fully considered and are persuasive. The objections to claims 1, 2, 4 and 16 have been withdrawn.
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.
Response to Arguments
Applicant's arguments filed 8/28/25 have been fully considered but they are not persuasive.
Applicant, page 9, refers to lines 6-8 of page 7 of the specification and argues that based on this, including a sentence reproduced on Remarks page 9 “all claims are in compliance with 35 U.S.C. 112.” However what is reproduced refers to a particular generally described method, which includes mixing “two solutions immiscible to each other, but made partially miscible by adding an alcohol or another proper solvent in each of them; in order to obtain a fine and homogenous molecular dispersion of the at least three components of the reinforcing mixture,” this set forth before the reproduced sentence. Taken in their entirety, this disclosure does not reasonably provide or indicate metes and bounds for what is claimed as statistically homogenous. There is no indication or limit on at what point the relevant particles or molecules of the composition coating the base matrix no longer are “statistically homogenous composition”, such as because there is a disproportionate or uneven distribution or dispersion of such relevant particles or molecules. The examiner reminds applicant that what is described on specification page 7, lines 1-8, pertain to a general method that is not claimed in claim 1, and that by its generality does not address what is, and what is not, “statistically homogenous.”
Claims 1-7, 10, and 13-18 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.
In claim 1, line 2, the use of “statistically homogenous” as this modifies composition renders the claim unclear and indefinite. There is no definition nor understanding by one of ordinary skill in the art as to what is “statistically homogenous” versus what is not “statistically homogenous”. Further, statistical confidence varies and can be selected by a user, here there is no indication of what are the limits of statistical significance as to what is “statistically homogenous”. As a result, the meaning is unclear and the metes and bounds of what is claimed are not reasonably determinable by one of ordinary skill in the art.
Accordingly, claim 1, and claims 2-7, 10 and 13-18 are rejected on this basis.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Response to Arguments
Applicant's arguments filed 8/28/25 have been fully considered but they are not persuasive.
Applicant argues against the 35 U.S.C. 103 obviousness rejection from pages 9-18.
The examiner responds as follows:
Regarding page 10 arguments alleging “misleading because it is incomplete” as to the P6 peptide in the ‘923 being effective to increase Bmp2, the data stands on its own, and a complete understanding of the particular pathways and mechanisms is not required to support the examiner’s statements, at least given the data in the ‘923 for the P6 peptide treatment.
Further, it is irrelevant that “the present invention does not claim BMP-2 effects” (even though applicant admits that in the present invention “the BMP-2 mRNA signal is used as a confirmation that a part of the cascade had been initiated.”)
The statements in the rejection about the P6 peptide results in the ‘923 stand on reasonable bases as to promoting bone formation, including as evidenced by Cho. The examiner affords very little weight to applicant’s argument at the bottom of page 10 as to “no inventive link” because the statements and data from the ‘923 regarding BMP-2 are only part of the reasonable basis for one of ordinary skill in the art to recognize the value of P6 peptide in bone formation. As set forth clearly in the rejection below, in addition to results regarding BMP-2, “all peptides significantly induced osteocalcin, taught in the ‘923 as the most specific and the latest of expressed osteoblast markers with a role in mineralization, this after 14 and 21 days of treatment with the formulated synthetic peptides compared to untreated and EMD alginate gel.” Applicant’s focus only on BMP-2 is misplaced and misses the overall teachings and bases for combining references’ teachings and components.
Regarding statements and assertions on page 11, the examiner never stated that BMP-2 is “the effector in the system”, and as to BMP-2’s expression regardless of applicant’s statement that this is expressed during all types of healing, the relevance to regarding the ‘923’s P6 treatment is the higher level of BMP-2 would reasonably suggest to one of ordinary skill in the art that P6 provides a benefit for bone formation. This is not the only reported increase of a relevant chemical for bone growth and formation, see rejection below, which also states the effect on osteocalcin (see quote above and please note that the examiner has added underlined emphases to indicate multiple effects).
Also on page 11 applicant begins a line of argument to distinguish what is claims from other coatings’ components.
First, as to a statement on page 12, although the ‘923 evaluates a particular alginate coated scaffold, the teachings of the effects of the peptides evaluated therein are 1) not compulsorily only combinable with that alginate-based matrix; and 2) would reasonably, to one of ordinary skill in the art, be understood to be transferable to other matrices comprising other component combinations practiced in the art, at least based on the effects demonstrated by the particular evaluated peptides in the ‘923.
Applicant strenuously argues that the effects of the proline-rich peptides, common to the ‘923 (and prior reference referred to in the ‘923) and the instant application, somehow achieve greater technical effects in the instant application’s claimed invention that are not suggested in the prior art ‘923.
Regarding multiple arguments and quotations from references including Rubert, pages 12-14, 1) although the ‘923 and Rubert focus on an alginate coating on titanium, the effects of the proline rich peptides are reasonably understood to not be limited to only performing well in such a system (see more below); and 2) at multiple points applicant makes strong assertions without sufficient reasoning, therefore little weight is given to these statements:
At top of page 13, there is insufficient basis to state, “Any well-founded evidence or prior art does not support it” – the bases in the rejection are reasonable and provide sufficient support for combining the references’ teachings as set forth in the rejection.
At top of page 14, there is no strong evidence or basis to conclude that “any activity of P2 concerning osteointegration and bone repair ability, if present, is limited to the co-existence of titanium oxide scaffold coated with alginate in combination with synthetic peptides rich in polyproline sequences, such as P2.” Rubert’s reference to an earlier study is taken far out of context, as are statements regarding the use of the titanium/alginate combination with the peptides.
In particular, Rubert (2012) at pages 1775 to 1776 states the following regarding differences in results including regarding an early 2D study:
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Clearly Rubert teaches that “the synthetic peptides rich in polyproline sequences have repetitively showed an increase in osteocalcin mRNA levels, both in vitro and in in vivo studies where titanium implants were coated with the peptide [NOTE THAT THIS IS NOT STATED TO BE WITH ALGINATE], and further when loaded into an alginate hydrogel for their use as a carrier for local delivery.” All of this supports the last sentence’s suggestion, but the last sentence cannot reasonably be taken, in view of the prior statements of results, to indicate that the only use of such peptides must be in the alginate system, or the alginate-coated titanium construct. To reach such conclusion as applicant attempts is to ignore clear statements of broader demonstrated effects for these peptides.
Similarly, in view of the entire article, the quoted conclusion at the bottom of page 13 of Remarks is properly viewed as Rubert’s focus on what it had demonstrated, not as a limiting statement of use for the peptides it just above this conclusion noted had been demonstrated effective in in vitro and in vivo studies not limited to alginate-coated TiO2 SC.
With regard to assertions and to data in provided references with regard to alleged unexpected results and/or synergies, the examiner states the following:
A certain amount of improvement would be reasonably expected when incorporating one or more proline-rich (polyproline) peptides taught as beneficial in the ‘923 (which also refers back to another reference, WO 2008/078167, teaching such peptides to induce biomineralizatio) into the Pertici bone implant matrix, which shares with the claimed composition 1, 2a and 2b as set forth in the rejection below;
The examiner has considered the data in the references provided with the Remarks and attributes little weight to the evidence that the citations on page 15 and their data perform beyond what would be reasonably expected improvement when adding the noted peptides known in the art, such as in the ‘923, to improve bone growth and formation, to the Pertici bone implant matrix.
In particular, the data in Zhu pertains to cells of 3 donors in cell media
As to any importance of being disordered peptides, this is inherent in the same peptides as taught and evaluated in the ‘923.
As well-stated in the 6/7/2024 Response to similar arguments, regarding in particular applicant’s assertion of unexpected results:
The Applicant concludes that D2/D3 teach that P2 affects osteointegration and bone
repair ability, but only when combined with a titanium oxide scaffold coated with
alginate, and that there is no pointer that P2 or P6 would affect osteointegration and
bone repair in combination with a scaffold different from titanium dioxide and/or a
scaffold coating different from alginate.
The Examining Division cannot follow this reasoning. The documents compare a
titanium oxide scaffold coated with alginate only, and a titanium oxide scaffold coated
with alginate and P2/P6, and show that the effect of the peptides is an improvement in
osteointegration. There is no indication in D2/D3 that this beneficial effect would not be
achieved with different coatings and/or scaffold materials. On the contrary, D2 teaches
that a variety of polymers can be used instead of alginate (see e.g. claim 9), including
biodegradable polyesters. The Applicant refers to the last paragraph of the right column
on page 1775, indicating that P2 did not induce expression of the same markers in
osteoblastic cells growing on 2% alginate in a 2D system, i.e. without the titanium oxide
scaffold, and from this statement concludes that a scaffold other than titanium will not
have the same effect according to D3. However, this passage in D3 only indicates that
the cells should be grown in a 3D system instead of a 2D system, and not that the
scaffold has to be formed from titanium oxide. The use of a scaffold, as in documents
D1 and D2, implicitly means the use of a 3D system. The only teaching that can be
taken away from documents D2 and D3 is thus that the addition of P2/P6 to a coating
composition on a scaffold provides said scaffold with improved osteointegration-properties.
The teaching of documents D4-D7 is similar: each of these documents makes use of a
commercially available xeno-hybrid bone graft, consisting of bovine bone-derived
mineral matrix which is improved by reinforcement with a biodegradable polyester
coating and the addition of RGD-exposing collagen fragments from animal-derived
gelatine. The peptides P2 and P6 are incorporated in this coating, and again it is shown
that such modified bone grafts have an improved osteogenic potential.
- However, from these documents D3-D7, it cannot be derived that there is any
synergistic effect, as suggested by the Applicant. It is common knowledge that
incorporating an active agent, e.g. a peptide, in a coating, provides sustained and
controlled release of said active agent. No further data were provided to compare the
osteogenic potential of the same bone graft coated with alginate and the praline-rich
peptides, with only gelatin and the praline-rich peptides, with only biodegradable
polyesters and the praline-rich peptides, and with the combination as now claimed and
said peptides, from which it can be concluded that the osteogenic effect of this specific
combination as now claimed is greater than what would be expected based on what is
already known from the prior art, e.g. documents D2 or D3, i.e. greater than the sum of
the technical effects of the individual features. Without further experimental data
convincingly demonstrating the alleged synergistic effect, the only technical effect that
can be taken into consideration is the improved osseointegration of the bone implant
matrix. The alleged synergistic effects of the claimed combination is thus considered not
to be supported by the documents cited by the Applicant, or by the application itself. In
the absence of evidence that the combined use of a biodegradable polyester, gelatin,
and the praline-rich peptides exerts unexpected effects over the known beneficial use of
said kinds of agents when used alone, no inventive step can be recognised for the
claimed subject matter. Moreover, if comparative tests are chosen to demonstrate an
inventive step resulting from an improved effect, the nature of the comparison with the
closest state of the art must be such that said effect is convincingly shown to have its
origin in the distinguishing feature.
In concluding this Response to Arguments, the examiner notes that the two major thrusts – to regard the effects of the peptides in the ‘923 as being only specific to that references matrix (which the cited references in it dispel at the outset), and to assert a particular effect found only when adding the same peptides to the Pertici matrix, here also asserting unique properties and unexpected synergies, are contrary to what would reasonably be expected on a plain reading of the references when considering the state and knowledge in the art at the time of applicant’s filing of its application. Although the ‘923 focuses on a particular alginate matrix over titanium, the effects of the evaluate peptides would not reasonably be understood by one of ordinary skill in the art to be limited only when added to such composition. This line of reasoning by applicant is specifically rebutted in the excerpt above and by this examiner. Particularly given the teachings of a list of additives in Pertici, one or ordinary skill in the art would reasonably have been motivated to evaluate and develop improved Pertici-type matrices by adding such peptides, with a very reasonable expectation of success.
Claim(s) 1-7, 10, and 13-18 are/remain rejected under 35 U.S.C. 103 as being unpatentable over WO 2010/070416, inventor Gianni Pertici, published 6/24/2010, (“Pertici”), provided in 9/24/21 IDS, in view of US 20150250923, inventors Lyngstadaas et al., published 9/10/2015 (“’923”), as evidenced by Cho et al., Tissue Engineering and Regenerative Medicine, Vol. 5, No. 3, pp 488-497 (“Cho”), (2008).
Claim 1 is directed to a bone implant matrix comprising a base matrix with a surface coated with a “statistically homogeneous composition which is a reinforcing mixture containing at least a soluble polymer”, at least a substance that stimulates cell proliferation and tissue integration selected from the group consisting of gelatine and hydrolyzed gelatine, and an artificial Proline-Rich Peptide selected from several alternative sub-genera peptide sequences set forth in the claim, underlining added to help to correspond to elected species.
The elected species of the claim 1 alternatives are:
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Pertici teaches a bone implant matrix and a reinforcing mixture containing at least a polymer, Abstract.
The following from Pertici teaches species of 1, 2a and 2b (underline emphases added):
From pages 7-8 as to a preference for acellularized non-demineralized bovine bone matrix:
The base matrix may be synthetic or natural. The
synthetic base matrixes may be, for example, polymeric,
metallic, ceramic, bio-ceramic, bio-glass matrixes.
Whereas, the natural base matrixes may be se-
(page break)
lected, for example, from demineralised bone, nondemineralised
bone, acellularised bone, natural polymeric,
mineral matrixes. As it is known, the acellularised
bone matrixes are non-demineralised matrixes
completely (or substantially) devoid of the donor's
cellular material.
Among the natural base matrixes which may be used
for carrying out the present invention, the human
corpse-derived bone matrixes are preferred and the
animal-derived demineralised, non-demineralised,
acellularised bone matrixes are particularly preferred,
in particular, preferably, bovine.
Further as to the preferred combination of elected species 1, 2a and 2b, from page 13, starting at line 6 (underline emphases added):
According to a further particularly preferred embodiment,
the bone implant matrix comprises a base
matrix, which is a bovine non-demineralised accellularised
bone matrix, treated with a reinforcing mixture
comprising a biodegradable polyester-based copolymer,
such as, for example, a poly(L-lactide-co-ε-caprolactone),
and preferably hydrolysed, gelatine.
The examiner notes that Pertici also uses the term “friendliness to cell” (now removed from claim 1) to indicate that this assists the cell rooting and growth, since the cell proliferation and the tissue integration are promoted and this is an important advantage in respect to the prior art (page 12). More particularly to the elected species of hydrolyzed gelatin(e), Pertici states its preference for this on page 12:
…and the use of gelatine, in particular hydrolysed, as "friendliness to cell" is particularly preferred. The presence of at least one "friendliness to cell" assists the cell rooting and growth, since the cell proliferation and the tissue integration are promoted and this is an important advantage in respect to the prior art.
As to the Pertici “reinforcing mixture” coating the surface of the bone implant matrix as required by claim 1, this requirement is clearly met based at least on the following from Pertici, this quotation also supporting that through the teachings of Pertici, one of ordinary skill in the art would understand that its reinforcing mixture would be “a statistically homogenous composition” as that term is best understood and interpreted (underline emphases added):
In particular, by the expression reinforcing mixture
it is meant a mixture, wherein the synthetic or
natural, and advantageously bio-compatible, polymer
or polymers, are finely dispersed.
Particularly preferred is a reinforcing mixture
obtained starting from two solutions, each of them
made of a soluble polymer and an agent promoting the
cell engraftment, growth and proliferation, and the
tissue integration, respectively, immiscible to each
other, but made partially miscible by adding an alcohol
or another proper solvent in each of them; in or~
der to obtain a fine and homogeneous molecular dispersion
of the components, which, during the solvent
evaporation step creates a homogeneous coating,
finely dispersed on the whole surf ace of the porous
bone matrix, i.e. coating it also in the inner cavities,
without closing them, though.
Pertici per the above, as well as elsewhere in its specification, clearly and unambiguously teaches the combination of a base matrix that is an acellularized non-demineralised bovine bone matrix, coated with a reinforcing mixture wherein its soluble polymer is poly(L-lactide-co-ε-caprolactone), and its “friendliness to cell” agent (now simply “substance” in claim 1, without “friendliness to cell”) is hydrolysed gelatine.
Although Pertici states, “According to another embodiment of the invention, the reinforcing mixture may comprise, beside the polymer or the polymers, at least an additional component selected from cell nutrients, cell-growth promoters, cell-adhesion promoters, osteoinductors, osteointegrators, "friendliness to cell", page 11, Pertici does not teach the addition of a Proline-Rich peptide, nor the Proline-Rich peptide corresponding to the elected SEQ ID NO:9.
The level of skill in the art is high, and there are substantial technological, biomedical and commercial motivations to improve known bone implant matrices by combining known therapeutic agents and materials found to have a beneficial effect.
The ‘923 teaches a titanium dioxide scaffold comprising a hydrogel coating comprising a biologically active substance, Abstract, and is in the same field of endeavor pertaining to providing implants or materials or biologically active agents for implants or matrices that can be surgically provided to a subject and help generate bone repair, see paras 2-12.
A particular teaching of a class of biologically active agents that the ‘923 teaches adding to its products is as follows (para numbers shown, underline emphases added):
[0122] Peptides and proteins suitable for incorporation into the hydrogel coating in particular include peptides and proteins known to affect cell growth and/or osseointegration of implants. A number of natural peptides have been shown to induce mineral precipitation and may therefore suitably be incorporated in the hydrogel coating. Examples include collagen 1 and 2, amelogenin, ameloblastin, bone sialoprotein, enamelin, and ansocalcin. Deposition and growth of apatites into endoskeletal mineralized tissues is a process guided by polyproline-rich proteins. Polyproline repeats are a common characteristic of hard tissue extracellular matrix proteins, playing a role on compaction of protein matrix, conformational variability, the apatite crystal length and bond to protein domains frequently involved in signaling events. For example, enamel matrix derivative (EMD) is an extract of porcine fetal tooth material used to biomimetically stimulate the soft and hard growth. EMD has also been proven to have a diversity of other biological activities, such as inhibition of inflammation and infection. A commercial product comprising EMD is Straumann.RTM.Emdogain (Straumann A G, Peter Merian-Weg 12, CH 4052 Basel, Switzerland). EMD contains a large amount of amelogenin, which is a protein that suitably may be incorporated into the hydrogel matrix, as mentioned above.
[0123] Further examples of peptides suitable for incorporation in the hydrogel coating include peptides based on the consensus peptides disclosed in WO 2008/078167, which induce biomineralization.
[0124] Peptides P2 (SEQ ID NO 1), P5 (SEQ ID NO 2) and P6 (SEQ ID NO 3), used in the experimental section, are examples of peptides based on the consensus sequences of WO 2008/078167 which may suitably be incorporated in the hydrogel coating. Other examples of such a sequence are P1 (SEQ ID NO 4: PLV PSY PLV PSY PLV PSY PYP PLPP), P3 (SEQ ID NO 5: PLV PSQ PLV PSQ PLV PSQ PQP PLPP) and P4 (SEQ ID NO 6: PLV PCC PLV PCC PLV PCC PCP PLPP).
The ’923 Example 1 evaluates SEQ ID Numbers 1, 2 and 3 in an alginate hydrogel, providing their sequences in Table 1, on page 11, identifying as “P6” the sequence corresponding to the ‘923 SEQ ID NO:3, which is identical with instant SEQ ID NO:9, the elected Proline-Rich peptide:
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.
Para 171 teaches, “Polyproline-rich synthetic peptides have previously been shown to induce bone formation and mineralization in vitro and to decrease bone resorption in vivo. The aim of this study was to develop a suitable formulation with a hydrogel for local treatment with these synthetic peptides to promote bone formation and mineralization, either alone or as a biodegradable coating for skeletal implants.”
After comparing results of a number of markers, the last three paragraphs of Example 1 are as follows:
[0178] On one hand it was found that osteocalcin, the most specific and the latest of expressed osteoblast markers with a role in mineralization, was significantly induced after 14 and 21 days of treatment with the formulated synthetic peptides compared to untreated and EMD alginate gel, i.e. in agreement with the results obtained when administered in the culture media. Accordingly, Opn, a sialoprotein produced at various stages of differentiation with higher levels expressed after mineralization has been initiated, was significantly up-regulated after 21 days of treatment with both EMD and synthetic peptides compared to control. On the other hand, at the time points studied, no differences were observed in the expression of genes related to osteogenesis (Coll-I, Bmp-2, Bsp and Alp), as these genes are regulated at earlier stages than osteocalcin during osteoblast differentiation, mainly in the proliferation and matrix maturation phase. It is interesting to note that all the studies that have been performed so far with the synthetic peptides have repetitively shown an increase in osteocalcin mRNA levels, both in vitro and in vivo. The relevance of this marker has been demonstrated in a recent in vivo study (Monjo M et al., 2012), where the best predictive marker for osseointegration of Ti implants among all was osteocalcin. It is suggested that the synthetic peptides improve the alginate hydrogel properties for cell attachment and that the cells cultured on the hydrogel formulated with synthetic peptides were at a more mature stage of the differentiation process over the cells cultured on control hydrogel and hydrogel formulated with EMD.
[0179] It may be hypothesized that the mode of action of the synthetic peptides might involve interaction with a receptor capable of influencing intracellular signaling cascades at the initial states of cell differentiation to finally stimulate osteoblast-differentiation and that the accessibility and structural rigidity of this short consensus sequence (PPXPP) may be of importance in the signaling activity of the synthetic peptides. Further, from the present results it is hypothesized that the peptides could bind to the integrins expressed on cell surface, which first could increase the osteoblast attachment on the alginate hydrogel surface and secondly modulate the expression of genes related with mature osteoblast phenotype.
Conclusion
[0180] In conclusion, the results demonstrate that 2% of alginate hydrogel is a suitable formulation for the local delivery of synthetic polyproline-rich peptides, inducing integrin alpha 8, osteopontin and osteocalcin expression in MC3T3-E1 cells. These peptide-modified alginate hydrogels may represent a new generation of injectable carriers with biologically active substance for bone tissue engineering applications and are promising for use as biodegradable coatings for skeletal implants, such as titanium dioxide scaffolds.
Although the ‘923 is focused on the suitability of its alginate hydrogels, a clear take-away from these teachings is that Proline-Rich peptides are active in bone regeneration through a number of specific effects and/or activities, and the P6 peptide was effective in increasing Bmp2 (bone morphogenic protein 2) mRNA levels, para 169 and Fig. 6A, statistically exceeding EMD at 14 days and numerically higher than P2 and P5 at 21 days. As evidenced by Cho, page 488, “Among BMPs, BMP-2 is known as the most effective cytokine, while recombinant human BMP-2(rhBMP-2) is useful in treating bony defects when combined with an adequate carrier system or matrix.” Additionally, all peptides significantly induced osteocalcin, taught in the ‘923 as the most specific and the latest of expressed osteoblast markers with a role in mineralization, this after 14 and 21 days of treatment with the formulated synthetic peptides compared to untreated and EMD alginate gel.
Based on these effects in the model of the ‘923, one of ordinary skill in the art would have been motivated to select a Proline-Rich peptide, such as and particularly the ‘923 SEQ ID NO:3 (~P6, and identical with the elected SEQ ID NO:9), as an additional bioactive agent in the reinforcing mixture of Pertici, meeting one or more of the properties or objectives of “…at least an additional component selected from cell nutrients, cell-growth promoters, cell-adhesion promoters, osteoinductors, osteointegrators, "friendliness to cell",” page 11. The rationale is combining prior art elements according to known methods to yield predictable results. Pertici teaches all components in combination except the Proline-Rich peptide, and the ‘923 teaches such peptides including the elected SEQ ID NO:9 as its SEQ ID NO:3. One of ordinary skill in the art, appreciating the beneficial effects of these peptides, including those of the ‘923 SEQ ID NO:3, could have combined the elements as claimed by known methods, teachings and practices, and that in combination, each element merely performs the same function as it does separately or when combined in known combinations. Based on the known and demonstrated properties of the components/elements, one of ordinary skill in the art would have recognized that the results of the combination were predictable. Also, there would have been a reasonable expectation of success given the teachings and results of the references, including the clear statement by the evidentiary reference Cho about the importance of BMP2 when considering the data from the ‘923.
Accordingly, claim 1, and claims 2-7, 10, 13-18 that depend from claim 1 directly or indirectly and comprise all components in combination rejected in claim 1, are rejected as obvious.1
For clarity:
Claims 2, 3, 4, 15, 16 as best understood each specify or include the elected poly(L-lactide-co-ε-caprolactone).
Claims 5, 6, 7, 13, 14, 17, 18 each include SEQ ID NO:9 as an alternative by itself, not requiring that this is in combination with another Proline-Rich peptide.
Claim 10 includes the elected and rejected as part of claim 1’s rejection acellularized non-demineralised bovine bone matrix.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7, 10, and 13-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4-8 of U.S. Patent No. 9770532, issued 9/26/2017, assignee INDUSTRIE BIOMEDICHE INSUBRI S/A (Reference patent), in view of US 20150250923, inventors Lyngstadaas et al., published 9/10/2015 (“’923”), as evidenced by Cho et al., Tissue Engineering and Regenerative Medicine, Vol. 5, No. 3, pp 488-497 (“Cho”), (2008).
Claim 1 is directed to a bone implant matrix comprising a base matrix with a surface coated with a “statistically homogeneous composition which is a reinforcing mixture containing at least a soluble polymer”, at least a substance [also identified by “friendliness to cell”] that stimulates cell proliferation and tissue integration selected from the group consisting of gelatine and hydrolyzed gelatine, and an artificial Proline-Rich Peptide selected from several alternative sub-genera peptide sequences set forth in the claim, underlining added to help to correspond to elected species.
The elected species of the claim 1 alternatives are:
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Reference patent claim 4 is directed to:
A bone implant matrix comprising: a base matrix treated with a reinforcing mixture as a homogeneous and finely dispersing coating, said reinforcing mixture containing at least a polymer, and at least an additional component selected from a “friendliness to cell:” a substance which promotes cell-rooting and cell growth by stimulating cell proliferation and tissue integration, wherein the base matrix is a bone demineralised or non-demineralised, bovine corpse-derived matrix, the polymer of the reinforcing mixture is a biodegradable polyester selected from the group consisting of polylactic acid (PLA), poliglycolic acid (PGA), polycaprolactone (PCL) and co-polymers thereof comprising polycaprolactone-polylactic (PLA/PCL) co-polymers and poly(L-lactide-co-εcapcolactone) co-polymers, poly(Llactide), poly(D,L-lactide-co-glycolide), poly(L-lactideco-D,L-lactide), their enantiomers, their co-polymers and mixtures thereof, the “friendliness to cell” is selected from the group consisting of gelatine, and hydrolysed gelatin, wherein the reinforcing mixture is obtained starting from two solutions, each of the solutions made of a soluble polymer comprising a biodegradable polyester, and an additional component comprising the gelatine or the hydrolysed gelatine, respectively, immiscible to each other, but made partially miscible by adding an alcohol or another proper solvent in order to obtain a fine polymer dispersion.
Reference patent claim 4’s bone implant matrix comprises instant claim 1’s elected species 1, 2a, and 2b, but does not comprise 2c.
The level of skill in the art is high, and there are substantial technological, biomedical and commercial motivations to improve known bone implant matrices by combining known therapeutic agents and materials found to have a beneficial effect.
The ‘923 teaches a titanium dioxide scaffold comprising a hydrogel coating comprising a biologically active substance, Abstract, and is in the same field of endeavor pertaining to providing implants or materials or biologically active agents for implants or matrices that can be surgically provided to a subject and help generate bone repair, see paras 2-12.
A particular teaching of a class of biologically active agents that the ‘923 teaches adding to its products is as follows (para numbers shown, underline emphases added):
[0122] Peptides and proteins suitable for incorporation into the hydrogel coating in particular include peptides and proteins known to affect cell growth and/or osseointegration of implants. A number of natural peptides have been shown to induce mineral precipitation and may therefore suitably be incorporated in the hydrogel coating. Examples include collagen 1 and 2, amelogenin, ameloblastin, bone sialoprotein, enamelin, and ansocalcin. Deposition and growth of apatites into endoskeletal mineralized tissues is a process guided by polyproline-rich proteins. Polyproline repeats are a common characteristic of hard tissue extracellular matrix proteins, playing a role on compaction of protein matrix, conformational variability, the apatite crystal length and bond to protein domains frequently involved in signaling events. For example, enamel matrix derivative (EMD) is an extract of porcine fetal tooth material used to biomimetically stimulate the soft and hard growth. EMD has also been proven to have a diversity of other biological activities, such as inhibition of inflammation and infection. A commercial product comprising EMD is Straumann.RTM.Emdogain (Straumann A G, Peter Merian-Weg 12, CH 4052 Basel, Switzerland). EMD contains a large amount of amelogenin, which is a protein that suitably may be incorporated into the hydrogel matrix, as mentioned above.
[0123] Further examples of peptides suitable for incorporation in the hydrogel coating include peptides based on the consensus peptides disclosed in WO 2008/078167, which induce biomineralization.
[0124] Peptides P2 (SEQ ID NO 1), P5 (SEQ ID NO 2) and P6 (SEQ ID NO 3), used in the experimental section, are examples of peptides based on the consensus sequences of WO 2008/078167 which may suitably be incorporated in the hydrogel coating. Other examples of such a sequence are P1 (SEQ ID NO 4: PLV PSY PLV PSY PLV PSY PYP PLPP), P3 (SEQ ID NO 5: PLV PSQ PLV PSQ PLV PSQ PQP PLPP) and P4 (SEQ ID NO 6: PLV PCC PLV PCC PLV PCC PCP PLPP).
The ’923 Example 1 evaluates SEQ ID Numbers 1, 2 and 3 in an alginate hydrogel, providing their sequences in Table 1, on page 11, identifying as “P6” the sequence corresponding to the ‘923 SEQ ID NO:3, which is identical with instant SEQ ID NO:9, the elected Proline-Rich peptide:
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Para 171 teaches, “Polyproline-rich synthetic peptides have previously been shown to induce bone formation and mineralization in vitro and to decrease bone resorption in vivo. The aim of this study was to develop a suitable formulation with a hydrogel for local treatment with these synthetic peptides to promote bone formation and mineralization, either alone or as a biodegradable coating for skeletal implants.”
After comparing results of a number of markers, the last three paragraphs of Example 1 are as follows:
[0178] On one hand it was found that osteocalcin, the most specific and the latest of expressed osteoblast markers with a role in mineralization, was significantly induced after 14 and 21 days of treatment with the formulated synthetic peptides compared to untreated and EMD alginate gel, i.e. in agreement with the results obtained when administered in the culture media. Accordingly, Opn, a sialoprotein produced at various stages of differentiation with higher levels expressed after mineralization has been initiated, was significantly up-regulated after 21 days of treatment with both EMD and synthetic peptides compared to control. On the other hand, at the time points studied, no differences were observed in the expression of genes related to osteogenesis (Coll-I, Bmp-2, Bsp and Alp), as these genes are regulated at earlier stages than osteocalcin during osteoblast differentiation, mainly in the proliferation and matrix maturation phase. It is interesting to note that all the studies that have been performed so far with the synthetic peptides have repetitively shown an increase in osteocalcin mRNA levels, both in vitro and in vivo. The relevance of this marker has been demonstrated in a recent in vivo study (Monjo M et al., 2012), where the best predictive marker for osseointegration of Ti implants among all was osteocalcin. It is suggested that the synthetic peptides improve the alginate hydrogel properties for cell attachment and that the cells cultured on the hydrogel formulated with synthetic peptides were at a more mature stage of the differentiation process over the cells cultured on control hydrogel and hydrogel formulated with EMD.
[0179] It may be hypothesized that the mode of action of the synthetic peptides might involve interaction with a receptor capable of influencing intracellular signaling cascades at the initial states of cell differentiation to finally stimulate osteoblast-differentiation and that the accessibility and structural rigidity of this short consensus sequence (PPXPP) may be of importance in the signaling activity of the synthetic peptides. Further, from the present results it is hypothesized that the peptides could bind to the integrins expressed on cell surface, which first could increase the osteoblast attachment on the alginate hydrogel surface and secondly modulate the expression of genes related with mature osteoblast phenotype.
Conclusion
[0180] In conclusion, the results demonstrate that 2% of alginate hydrogel is a suitable formulation for the local delivery of synthetic polyproline-rich peptides, inducing integrin alpha 8, osteopontin and osteocalcin expression in MC3T3-E1 cells. These peptide-modified alginate hydrogels may represent a new generation of injectable carriers with biologically active substance for bone tissue engineering applications and are promising for use as biodegradable coatings for skeletal implants, such as titanium dioxide scaffolds.
Although the ‘923 is focused on the suitability of its alginate hydrogels, a clear take-away from these teachings is that Proline-Rich peptides are active in bone regeneration through a number of specific effects and/or activities, and the P6 peptide was effective in increasing Bmp2 (bone morphogenic protein 2) mRNA levels, para 169 and Fig. 6A, statistically exceeding EMD at 14 days and numerically higher than P2 and P5 at 21 days. As evidenced by Cho, page 488, “Among BMPs, BMP-2 is known as the most effective cytokine, while recombinant human BMP-2(rhBMP-2) is useful in treating bony defects when combined with an adequate carrier system or matrix.” Additionally, all peptides significantly induced osteocalcin, taught in the ‘923 as the most specific and the latest of expressed osteoblast markers with a role in mineralization, this after 14 and 21 days of treatment with the formulated synthetic peptides compared to untreated and EMD alginate gel.
Based on these effects in the model of the ‘923, one of ordinary skill in the art would have been motivated to select a Proline-Rich peptide, such as and particularly the ‘923 SEQ ID NO:3 (~P6, and identical with the elected SEQ ID NO:9), as an additional bioactive agent in the bone implant matrix of Reference patent claim 4. The rationale is combining prior art elements according to known methods to yield predictable results. Reference patent claim 4 is directed to a bone implant matrix that comprises a bovine bone-derived matrix reinforced with at least one polymer, which includes poly(L-lactic-co-ε-caprolactone), and other components known in the art to be suitable for supporting bone regeneration. The ‘923 teaches proline-rich peptides including the elected SEQ ID NO:9 as its SEQ ID NO:3. One of ordinary skill in the art, appreciating the beneficial effects of these peptides, including those of the ‘923 SEQ ID NO:3, as well as the components set forth in Reference patent claim 4, as well as the narrower and ‘adapted for use’ claims of Reference patent claims 5-8, could have combined the elements as claimed by known methods, teachings and practices, and that in combination, each element merely performs the same function as it does separately or when combined in known combinations. Based on the known and demonstrated properties of the components/elements, one of ordinary skill in the art would have recognized that the results of the combination were predictable. Also, there would have been a reasonable expectation of success given the teachings and results of the references, including the clear statement by the evidentiary reference Cho about the importance of BMP2 when considering the data from the ‘923.
Accordingly, based on the rationale set forth above considering the Reference patent claims and the teachings of the secondary references, claim 1, and claims 2-7, 10, 13-18 that depend from claim 1 directly or indirectly and comprise all components in combination rejected in claim 1, are rejected under this section.
For clarity:
Claims 2, 3, 4, 15, 16 as best understood each specify or include the elected poly(L-lactide-co-ε-caprolactone), which the Reference patent claim 4 claims.
Claims 5, 6, 7, 13, 14, 17, 18 each include SEQ ID NO:9 as an alternative by itself, this identical to the ‘923 SEQ ID NO:3, not requiring that this is in combination with another Proline-Rich peptide.
Claim 10 includes the elected and rejected as part of claim 1’s rejection acellularized non-demineralised bovine bone matrix, which Reference patent claim 4 claims.
Claims 1-7, 10, 13-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6 of copending Application No. 18280757 (Reference application) in view of WO 2010/070416, inventor Gianni Pertici, published 6/24/2010, (“Pertici”), provided in 9/24/21 IDS, US 20150250923, inventors Lyngstadaas et al., published 9/10/2015 (“’923”), as evidenced by Cho et al., Tissue Engineering and Regenerative Medicine, Vol. 5, No. 3, pp 488-497 (“Cho”), (2008).
Claim 1 is directed to a bone implant matrix comprising a base matrix with a surface coated with a “statistically homogeneous composition which is a reinforcing mixture containing at least a soluble polymer”, at least a substance [also identified by “friendliness to cell”] that stimulates cell proliferation and tissue integration selected from the group consisting of gelatine and hydrolyzed gelatine, and an artificial Proline-Rich Peptide selected from several alternative sub-genera peptide sequences set forth in the claim, underlining added to help to correspond to elected species.
The elected species of the claim 1 alternatives are:
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Reference application claim 1 teaches a scaffold for bone regeneration comprising a support structure made with bovine bone-derived matrix reinforced with at least one polymer, this support structure also stated to be functionalized with secretome. The examiner notes that the meaning of “reinforced” per the Reference application includes coating, see paras 66 and 67.
As to one elected species, Reference patent claim 6, as best understood, claims that the bovine bone-derived matrix is reinforced (so coated) with poly(L-lactice-co[s, likely meaning epsilon]caprolactone).
Reference application claims do not claim gelatin or hydrolysed gelatine, nor any Proline-Rich peptide.
To the extent not all limitations nor specifically elected species are obvious over the Reference application claims a set forth above, Pertici teaches a bone implant matrix and a reinforcing mixture containing at least a polymer, Abstract.
The following from Pertici teaches species of 1, 2a and 2b (underline emphases added):
From pages 7-8 as to a preference for acellularized non-demineralized bovine bone matrix:
The base matrix may be synthetic or natural. The
synthetic base matrixes may be, for example, polymeric,
metallic, ceramic, bio-ceramic, bio-glass matrixes.
Whereas, the natural base matrixes may be se-
(page break)
lected, for example, from demineralised bone, nondemineralised
bone, acellularised bone, natural polymeric,
mineral matrixes. As it is known, the acellularised
bone matrixes are non-demineralised matrixes
completely (or substantially) devoid of the donor's
cellular material.
Among the natural base matrixes which may be used
for carrying out the present invention, the human
corpse-derived bone matrixes are preferred and the
animal-derived demineralised, non-demineralised,
acellularised bone matrixes are particularly preferred,
in particular, preferably, bovine.
Further as to the preferred combination of elected species 1, 2a and 2b, from page 13, starting at line 6 (underline emphases added):
According to a further particularly preferred embodiment,
the bone implant matrix comprises a base
matrix, which is a bovine non-demineralised accellularised
bone matrix, treated with a reinforcing mixture
comprising a biodegradable polyester-based copolymer,
such as, for example, a poly(L-lactide-co-ε-caprolactone),
and preferably hydrolysed, gelatine.
The examiner notes that Pertici also uses the term “friendliness to cell” to indicate that this assists the cell rooting and growth, since the cell proliferation and the tissue integration are promoted and this is an important advantage in respect to the prior art (page 12). More particularly to the elected species of hydrolyzed gelatin(e), Pertici states its preference for this on page 12:
…and the use of gelatine, in particular hydrolysed, as "friendliness to cell" is particularly preferred. The presence of at least one "friendliness to cell" assists the cell rooting and growth, since the cell proliferation and the tissue integration are promoted and this is an important advantage in respect to the prior art.
As to the Pertici “reinforcing mixture” coating the surface of the bone implant matrix as required by claim 1, this requirement is clearly met based at least on the following from Pertici, this quotation also supporting that through the teachings of Pertici, one of ordinary skill in the art would understand that its reinforcing mixture would be “a statistically homogenous composition” as that term is best understood and interpreted (underline emphases added):
In particular, by the expression reinforcing mixture
it is meant a mixture, wherein the synthetic or
natural, and advantageously bio-compatible, polymer
or polymers, are finely dispersed.
Particularly preferred is a reinforcing mixture
obtained starting from two solutions, each of them
made of a soluble polymer and an agent promoting the
cell engraftment, growth and proliferation, and the
tissue integration, respectively, immiscible to each
other, but made partially miscible by adding an alcohol
or another proper solvent in each of them; in or~
der to obtain a fine and homogeneous molecular dispersion
of the components, which, during the solvent
evaporation step creates a homogeneous coating,
finely dispersed on the whole surf ace of the porous
bone matrix, i.e. coating it also in the inner cavities,
without closing them, though.
Pertici per the above, as well as elsewhere in its specification, clearly and unambiguously teaches the combination of a base matrix, this considered equivalent to Reference application claim 1’s support structure, that is an acellularized non-demineralised bovine bone matrix, coated with a reinforcing mixture wherein its soluble polymer is poly(L-lactide-co-ε-caprolactone), and its “friendliness to cell” agent is hydrolysed gelatine.
Although Pertici states, “According to another embodiment of the invention, the reinforcing mixture may comprise, beside the polymer or the polymers, at least an additional component selected from cell nutrients, cell-growth promoters, cell-adhesion promoters, osteoinductors, osteointegrators, "friendliness to cell", page 11, Pertici does not teach the addition of a Proline-Rich peptide, nor the Proline-Rich peptide corresponding to the elected SEQ ID NO:9.
The level of skill in the art is high, and there are substantial technological, biomedical and commercial motivations to improve known bone implant matrices by combining known therapeutic agents and materials found to have a beneficial effect.
The ‘923 teaches a titanium dioxide scaffold comprising a hydrogel coating comprising a biologically active substance, Abstract, and is in the same field of endeavor pertaining to providing implants or materials or biologically active agents for implants or matrices that can be surgically provided to a subject and help generate bone repair, see paras 2-12.
A particular teaching of a class of biologically active agents that the ‘923 teaches adding to its products is as follows (para numbers shown, underline emphases added):
[0122] Peptides and proteins suitable for incorporation into the hydrogel coating in particular include peptides and proteins known to affect cell growth and/or osseointegration of implants. A number of natural peptides have been shown to induce mineral precipitation and may therefore suitably be incorporated in the hydrogel coating. Examples include collagen 1 and 2, amelogenin, ameloblastin, bone sialoprotein, enamelin, and ansocalcin. Deposition and growth of apatites into endoskeletal mineralized tissues is a process guided by polyproline-rich proteins. Polyproline repeats are a common characteristic of hard tissue extracellular matrix proteins, playing a role on compaction of protein matrix, conformational variability, the apatite crystal length and bond to protein domains frequently involved in signaling events. For example, enamel matrix derivative (EMD) is an extract of porcine fetal tooth material used to biomimetically stimulate the soft and hard growth. EMD has also been proven to have a diversity of other biological activities, such as inhibition of inflammation and infection. A commercial product comprising EMD is Straumann.RTM.Emdogain (Straumann A G, Peter Merian-Weg 12, CH 4052 Basel, Switzerland). EMD contains a large amount of amelogenin, which is a protein that suitably may be incorporated into the hydrogel matrix, as mentioned above.
[0123] Further examples of peptides suitable for incorporation in the hydrogel coating include peptides based on the consensus peptides disclosed in WO 2008/078167, which induce biomineralization.
[0124] Peptides P2 (SEQ ID NO 1), P5 (SEQ ID NO 2) and P6 (SEQ ID NO 3), used in the experimental section, are examples of peptides based on the consensus sequences of WO 2008/078167 which may suitably be incorporated in the hydrogel coating. Other examples of such a sequence are P1 (SEQ ID NO 4: PLV PSY PLV PSY PLV PSY PYP PLPP), P3 (SEQ ID NO 5: PLV PSQ PLV PSQ PLV PSQ PQP PLPP) and P4 (SEQ ID NO 6: PLV PCC PLV PCC PLV PCC PCP PLPP).
The ’923 Example 1 evaluates SEQ ID Numbers 1, 2 and 3 in an alginate hydrogel, providing their sequences in Table 1, on page 11, identifying as “P6” the sequence corresponding to the ‘923 SEQ ID NO:3, which is identical with instant SEQ ID NO:9, the elected Proline-Rich peptide:
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Para 171 teaches, “Polyproline-rich synthetic peptides have previously been shown to induce bone formation and mineralization in vitro and to decrease bone resorption in vivo. The aim of this study was to develop a suitable formulation with a hydrogel for local treatment with these synthetic peptides to promote bone formation and mineralization, either alone or as a biodegradable coating for skeletal implants.”
After comparing results of a number of markers, the last three paragraphs of Example 1 are as follows:
[0178] On one hand it was found that osteocalcin, the most specific and the latest of expressed osteoblast markers with a role in mineralization, was significantly induced after 14 and 21 days of treatment with the formulated synthetic peptides compared to untreated and EMD alginate gel, i.e. in agreement with the results obtained when administered in the culture media. Accordingly, Opn, a sialoprotein produced at various stages of differentiation with higher levels expressed after mineralization has been initiated, was significantly up-regulated after 21 days of treatment with both EMD and synthetic peptides compared to control. On the other hand, at the time points studied, no differences were observed in the expression of genes related to osteogenesis (Coll-I, Bmp-2, Bsp and Alp), as these genes are regulated at earlier stages than osteocalcin during osteoblast differentiation, mainly in the proliferation and matrix maturation phase. It is interesting to note that all the studies that have been performed so far with the synthetic peptides have repetitively shown an increase in osteocalcin mRNA levels, both in vitro and in vivo. The relevance of this marker has been demonstrated in a recent in vivo study (Monjo M et al., 2012), where the best predictive marker for osseointegration of Ti implants among all was osteocalcin. It is suggested that the synthetic peptides improve the alginate hydrogel properties for cell attachment and that the cells cultured on the hydrogel formulated with synthetic peptides were at a more mature stage of the differentiation process over the cells cultured on control hydrogel and hydrogel formulated with EMD.
[0179] It may be hypothesized that the mode of action of the synthetic peptides might involve interaction with a receptor capable of influencing intracellular signaling cascades at the initial states of cell differentiation to finally stimulate osteoblast-differentiation and that the accessibility and structural rigidity of this short consensus sequence (PPXPP) may be of importance in the signaling activity of the synthetic peptides. Further, from the present results it is hypothesized that the peptides could bind to the integrins expressed on cell surface, which first could increase the osteoblast attachment on the alginate hydrogel surface and secondly modulate the expression of genes related with mature osteoblast phenotype.
Conclusion
[0180] In conclusion, the results demonstrate that 2% of alginate hydrogel is a suitable formulation for the local delivery of synthetic polyproline-rich peptides, inducing integrin alpha 8, osteopontin and osteocalcin expression in MC3T3-E1 cells. These peptide-modified alginate hydrogels may represent a new generation of injectable carriers with biologically active substance for bone tissue engineering applications and are promising for use as biodegradable coatings for skeletal implants, such as titanium dioxide scaffolds.
Although the ‘923 is focused on the suitability of its alginate hydrogels, a clear take-away from these teachings is that Proline-Rich peptides are active in bone regeneration through a number of specific effects and/or activities, and the P6 peptide was effective in increasing Bmp2 (bone morphogenic protein 2) mRNA levels, para 169 and Fig. 6A, statistically exceeding EMD at 14 days and numerically higher than P2 and P5 at 21 days. As evidenced by Cho, page 488, “Among BMPs, BMP-2 is known as the most effective cytokine, while recombinant human BMP-2(rhBMP-2) is useful in treating bony defects when combined with an adequate carrier system or matrix.” Additionally, all peptides significantly induced osteocalcin, taught in the ‘923 as the most specific and the latest of expressed osteoblast markers with a role in mineralization, this after 14 and 21 days of treatment with the formulated synthetic peptides compared to untreated and EMD alginate gel.
Based on these effects in the model of the ‘923, one of ordinary skill in the art would have been motivated to select a Proline-Rich peptide, such as and particularly the ‘923 SEQ ID NO:3 (~P6, and identical with the elected SEQ ID NO:9), as an additional bioactive agent in the reinforcing mixture of Pertici and also to combine with Reference application claim 1’s components, meeting one or more of the properties or objectives of “…at least an additional component selected from cell nutrients, cell-growth promoters, cell-adhesion promoters, osteoinductors, osteointegrators, "friendliness to cell", page 11.” The rationale is combining prior art elements according to known methods to yield predictable results. Reference application claim 1 is directed to a scaffold for bone regeneration that comprises a bovine bone-derived matrix reinforced with at least one polymer, which can be as best understood poly(L-lactice-co-ε-caprolactone), and other components known in the art to be suitable for supporting bone regeneration and cells associated with the same. Pertici in the same field teaches all instantly claimed components in combination except the Proline-Rich peptide, and the ‘923 teaches such peptides including the elected SEQ ID NO:9 as its SEQ ID NO:3. One of ordinary skill in the art, appreciating the beneficial effects of these peptides, including those of the ‘923 SEQ ID NO:3, as well as the components set forth in Pertici, could have combined the elements as claimed by known methods, teachings and practices, and that in combination, each element merely performs the same function as it does separately or when combined in known combinations. Based on the known and demonstrated properties of the components/elements, one of ordinary skill in the art would have recognized that the results of the combination were predictable. Also, there would have been a reasonable expectation of success given the teachings and results of the references, including the clear statement by the evidentiary reference Cho about the importance of BMP2 when considering the data from the ‘923.
Accordingly, based on the rationale set forth above considering the Reference application claims and the teachings of the secondary references, claim 1, and claims 2-7, 10, 13-18 that depend from claim 1 directly or indirectly and comprise all components in combination rejected in claim 1, are rejected under this section.
For clarity:
Claims 2, 3, 4, 15, 16 as best understood each specify or include the elected poly(L-lactide-co-ε-caprolactone).
Claims 5, 6, 7, 13, 14, 17, 18 each include SEQ ID NO:9 as an alternative by itself, not requiring that this is in combination with another Proline-Rich peptide.
Claim 10 includes the elected and rejected as part of claim 1’s rejection acellularized non-demineralised bovine bone matrix.
This is a provisional nonstatutory double patenting rejection.
Claims 1-7, 10, and 13-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3 of U.S. Patent Application No. 19497591, in view of U.S. Patent No. 9770532, issued 9/26/2017, assignee INDUSTRIE BIOMEDICHE INSUBRI S/A (“Industry”).
Claim 1 is directed to a bone implant matrix comprising a base matrix with a surface coated with a “statistically homogeneous composition which is a reinforcing mixture containing at least a soluble polymer”, at least a substance [also identified by “friendliness to cell”] that stimulates cell proliferation and tissue integration selected from the group consisting of gelatine and hydrolyzed gelatine, and an artificial Proline-Rich Peptide selected from several alternative sub-genera peptide sequences set forth in the claim, underlining added to help to correspond to elected species.
The elected species of the claim 1 alternatives are:
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Reference application claim 1 claims a pharmaceutical formulation in the form of a gel comprising an artificial peptide in generic form and linear hyaluronic acid fibers, and claim 3 specifically claims SEQ ID NO:5 as one of the artificial peptides (at least 90% identical to this, so including this itself), that SEQ ID NO:5 identical with instant SEQ ID NO:9, so these reference application claims claim instant 2c, but do not teach or claim 1, 2a or 2b.
The level of skill in the art is high, and there are substantial technological, biomedical and commercial motivations to improve known bone implant matrices by combining known therapeutic agents and materials found to have a beneficial effect.
Industry claim 4 is directed to:
A bone implant matrix comprising: a base matrix treated with a reinforcing mixture as a homogeneous and finely dispersing coating, said reinforcing mixture containing at least a polymer, and at least an additional component selected from a “friendliness to cell:” a substance which promotes cell-rooting and cell growth by stimulating cell proliferation and tissue integration, wherein the base matrix is a bone demineralised or non-demineralised, bovine corpse-derived matrix, the polymer of the reinforcing mixture is a biodegradable polyester selected from the group consisting of polylactic acid (PLA), poliglycolic acid (PGA), polycaprolactone (PCL) and co-polymers thereof comprising polycaprolactone-polylactic (PLA/PCL) co-polymers and poly(L-lactide-co-εcapcolactone) co-polymers, poly(Llactide), poly(D,L-lactide-co-glycolide), poly(L-lactideco-D,L-lactide), their enantiomers, their co-polymers and mixtures thereof, the “friendliness to cell” is selected from the group consisting of gelatine, and hydrolysed gelatin, wherein the reinforcing mixture is obtained starting from two solutions, each of the solutions made of a soluble polymer comprising a biodegradable polyester, and an additional component comprising the gelatine or the hydrolysed gelatine, respectively, immiscible to each other, but made partially miscible by adding an alcohol or another proper solvent in order to obtain a fine polymer dispersion.
Industry claim 4’s bone implant matrix comprises instant claim 1’s elected species 1, 2a, and 2b.
Regarding use of the Reference application claimed formulations, in particular the artificial peptides characterized by a proline sequence, as evidenced in the Reference application specification, page 1, lines 5-8, these were known in the art “to partake in wound healing as well as in bone and cartilage formation and connective tissue maintenance in vertebrates and their uses in medicine.”
One of ordinary skill in the art could have combined the elements as claimed by known methods, teachings and practices, and that in combination, each element merely performs the same function as it does separately or when combined in known combinations, with the objective to obtain an improved product including the proline rich peptides. Based on the known properties of the components/elements, one of ordinary skill in the art would have recognized that the results of the combination were predictable. Also, there would have been a reasonable expectation of success given the teachings and results of the references.
Accordingly, based on the rationale set forth above considering the Reference patent claims and the teachings of the secondary references, claim 1, and claims 2-7, 10, 13-18 that depend from claim 1 directly or indirectly and comprise all components in combination rejected in claim 1, are rejected under this section.
For clarity:
Claims 2, 3, 4, 15, 16 as best understood each specify or include the elected poly(L-lactide-co-ε-caprolactone), which the Industry claim 4 claims.
Claims 5, 6, 7, 13, 14, 17, 18 each include SEQ ID NO:9 as an alternative by itself, this identical to the Reference Application claim 3 SEQ ID NO:5, not requiring that this is in combination with another Proline-Rich peptide.
Claim 10 includes the elected and rejected as part of claim 1’s rejection acellularized non-demineralised bovine bone matrix, which Industry claim 4 claims.
This is a provisional nonstatutory double patenting rejection.
Claims 1-7, 10, and 13-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3 of U.S. Patent Application No. 19497597, in view of U.S. Patent No. 9770532, issued 9/26/2017, assignee INDUSTRIE BIOMEDICHE INSUBRI S/A (“Industry”).
Claim 1 is directed to a bone implant matrix comprising a base matrix with a surface coated with a “statistically homogeneous composition which is a reinforcing mixture containing at least a soluble polymer”, at least a substance [also identified by “friendliness to cell”] that stimulates cell proliferation and tissue integration selected from the group consisting of gelatine and hydrolyzed gelatine, and an artificial Proline-Rich Peptide selected from several alternative sub-genera peptide sequences set forth in the claim, underlining added to help to correspond to elected species.
The elected species of the claim 1 alternatives are:
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Reference application claim 1 claims a pharmaceutical formulation in the form of a gel comprising an artificial peptide in generic form and linear hyaluronic acid fibers (with a stated “for use in treating an inflamed degenerated or damaged joint”), and claim 3 specifically claims SEQ ID NO:5 as one of the artificial peptides (at least 90% identical to this, so including this itself), that SEQ ID NO:5 identical with instant SEQ ID NO:9, so these reference application claims claim instant 2c, but do not teach or claim 1, 2a or 2b.
The level of skill in the art is high, and there are substantial technological, biomedical and commercial motivations to improve known bone implant matrices by combining known therapeutic agents and materials found to have a beneficial effect.
Industry claim 4 is directed to:
A bone implant matrix comprising: a base matrix treated with a reinforcing mixture as a homogeneous and finely dispersing coating, said reinforcing mixture containing at least a polymer, and at least an additional component selected from a “friendliness to cell:” a substance which promotes cell-rooting and cell growth by stimulating cell proliferation and tissue integration, wherein the base matrix is a bone demineralised or non-demineralised, bovine corpse-derived matrix, the polymer of the reinforcing mixture is a biodegradable polyester selected from the group consisting of polylactic acid (PLA), poliglycolic acid (PGA), polycaprolactone (PCL) and co-polymers thereof comprising polycaprolactone-polylactic (PLA/PCL) co-polymers and poly(L-lactide-co-εcapcolactone) co-polymers, poly(Llactide), poly(D,L-lactide-co-glycolide), poly(L-lactideco-D,L-lactide), their enantiomers, their co-polymers and mixtures thereof, the “friendliness to cell” is selected from the group consisting of gelatine, and hydrolysed gelatin, wherein the reinforcing mixture is obtained starting from two solutions, each of the solutions made of a soluble polymer comprising a biodegradable polyester, and an additional component comprising the gelatine or the hydrolysed gelatine, respectively, immiscible to each other, but made partially miscible by adding an alcohol or another proper solvent in order to obtain a fine polymer dispersion.
Industry claim 4’s bone implant matrix comprises instant claim 1’s elected species 1, 2a, and 2b.
Regarding use of the Reference application claimed formulations, in particular the artificial peptides characterized by a proline sequence, as evidenced in the Reference application specification, page 1, lines 6-9, these were known in the art “to partake in wound healing as well as in bone and cartilage formation and connective tissue maintenance in vertebrates and their uses in medicine.”
One of ordinary skill in the art could have combined the elements as claimed by known methods, teachings and practices, and that in combination, each element merely performs the same function as it does separately or when combined in known combinations, with the objective to obtain an improved product including the proline rich peptides. Based on the known properties of the components/elements, one of ordinary skill in the art would have recognized that the results of the combination were predictable. Also, there would have been a reasonable expectation of success given the teachings and results of the references.
Accordingly, based on the rationale set forth above considering the Reference patent claims and the teachings of the secondary references, claim 1, and claims 2-7, 10, 13-18 that depend from claim 1 directly or indirectly and comprise all components in combination rejected in claim 1, are rejected under this section.
For clarity:
Claims 2, 3, 4, 15, 16 as best understood each specify or include the elected poly(L-lactide-co-ε-caprolactone), which the Industry claim 4 claims.
Claims 5, 6, 7, 13, 14, 17, 18 each include SEQ ID NO:9 as an alternative by itself, this identical to the Reference Application claim 3 SEQ ID NO:5, not requiring that this is in combination with another Proline-Rich peptide.
Claim 10 includes the elected and rejected as part of claim 1’s rejection acellularized non-demineralised bovine bone matrix, which Industry claim 4 claims.
Claims 1-7, 10, and 13-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3 of U.S. Patent Application No. 19497666, in view of U.S. Patent No. 9770532, issued 9/26/2017, assignee INDUSTRIE BIOMEDICHE INSUBRI S/A (“Industry”).
Claim 1 is directed to a bone implant matrix comprising a base matrix with a surface coated with a “statistically homogeneous composition which is a reinforcing mixture containing at least a soluble polymer”, at least a substance [also identified by “friendliness to cell”] that stimulates cell proliferation and tissue integration selected from the group consisting of gelatine and hydrolyzed gelatine, and an artificial Proline-Rich Peptide selected from several alternative sub-genera peptide sequences set forth in the claim, underlining added to help to correspond to elected species.
The elected species of the claim 1 alternatives are:
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Reference application claim 1 claims a pharmaceutical formulation in the form of a gel comprising an artificial peptide in generic form and linear hyaluronic acid fibers (with a stated “for use in viscosupplementation”, this not materially affecting the claimed structure of what is claimed), and claim 3 specifically claims SEQ ID NO:5 as one of the artificial peptides (at least 90% identical to this, so including this itself), that SEQ ID NO:5 identical with instant SEQ ID NO:9, so these reference application claims claim instant 2c, but do not teach or claim 1, 2a or 2b.
The level of skill in the art is high, and there are substantial technological, biomedical and commercial motivations to improve known bone implant matrices by combining known therapeutic agents and materials found to have a beneficial effect.
Industry claim 4 is directed to:
A bone implant matrix comprising: a base matrix treated with a reinforcing mixture as a homogeneous and finely dispersing coating, said reinforcing mixture containing at least a polymer, and at least an additional component selected from a “friendliness to cell:” a substance which promotes cell-rooting and cell growth by stimulating cell proliferation and tissue integration, wherein the base matrix is a bone demineralised or non-demineralised, bovine corpse-derived matrix, the polymer of the reinforcing mixture is a biodegradable polyester selected from the group consisting of polylactic acid (PLA), poliglycolic acid (PGA), polycaprolactone (PCL) and co-polymers thereof comprising polycaprolactone-polylactic (PLA/PCL) co-polymers and poly(L-lactide-co-εcapcolactone) co-polymers, poly(Llactide), poly(D,L-lactide-co-glycolide), poly(L-lactideco-D,L-lactide), their enantiomers, their co-polymers and mixtures thereof, the “friendliness to cell” is selected from the group consisting of gelatine, and hydrolysed gelatin, wherein the reinforcing mixture is obtained starting from two solutions, each of the solutions made of a soluble polymer comprising a biodegradable polyester, and an additional component comprising the gelatine or the hydrolysed gelatine, respectively, immiscible to each other, but made partially miscible by adding an alcohol or another proper solvent in order to obtain a fine polymer dispersion.
Industry claim 4’s bone implant matrix comprises instant claim 1’s elected species 1, 2a, and 2b.
Regarding use of the Reference application claimed formulations, in particular the artificial peptides characterized by a proline sequence, as evidenced in the Reference application specification, page 1, lines 6-9, these were known in the art “to partake in wound healing as well as in bone and cartilage formation and connective tissue maintenance in vertebrates and their uses in medicine.”
One of ordinary skill in the art could have combined the elements as claimed by known methods, teachings and practices, and that in combination, each element merely performs the same function as it does separately or when combined in known combinations, with the objective to obtain an improved product including the proline rich peptides. Based on the known properties of the components/elements, one of ordinary skill in the art would have recognized that the results of the combination were predictable. Also, there would have been a reasonable expectation of success given the teachings and results of the references.
Accordingly, based on the rationale set forth above considering the Reference patent claims and the teachings of the secondary references, claim 1, and claims 2-7, 10, 13-18 that depend from claim 1 directly or indirectly and comprise all components in combination rejected in claim 1, are rejected under this section.
For clarity:
Claims 2, 3, 4, 15, 16 as best understood each specify or include the elected poly(L-lactide-co-ε-caprolactone), which the Industry claim 4 claims.
Claims 5, 6, 7, 13, 14, 17, 18 each include SEQ ID NO:9 as an alternative by itself, this identical to the Reference Application claim 3 SEQ ID NO:5, not requiring that this is in combination with another Proline-Rich peptide.
Claim 10 includes the elected and rejected as part of claim 1’s rejection acellularized non-demineralised bovine bone matrix, which Industry claim 4 claims.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
1 The examiner notes that instant SEQ ID NO:4 is identical to the ‘923 SEQ ID NO:1, however claims directed specifically to SEQ ID NO:4 or combinations including this sequence, having being withdrawn based on species election of SEQ ID NO:9, are not currently rejected.